Schizophrenia Research 192 (2018) 9–15

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Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Grey matter reduction in the caudate nucleus in patients with persistent

negative symptoms: An ALE meta-analysis
Ying Li a,b,c, Wen-xiu Li c, Dong-jie Xie a,b, Yi Wang a, Eric F.C. Cheung d, Raymond C.K. Chan a,b,⁎
a
Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China
b
University of Chinese Academy of Sciences, Beijing, China
c
Haidian District Mental Health Prevent-Treatment Hospital, Beijing, China
d
Castle Peak Hospital, Hong Kong Special Administration Region, China

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: In the present study, we used Activation Likelihood Estimation (ALE) meta-analysis to quantitatively
Received 28 October 2016 examine brain grey matter reduction in schizophrenia patients with persistent negative symptoms (PNS).
Received in revised form 20 March 2017 Method: A total of 12 voxel-based morphometry (VBM) studies were included in ALE meta-analysis using more
Accepted 1 April 2017 stringent criterion of PNS.
Available online 5 April 2017
Results: Significant grey matter reduction in the PNS group relative to controls was observed in the left caudate
nucleus, the left precentral region, the left middle frontal region, the bilateral parahippocampal region, the left
Keywords:
Meta-analysis
anterior cingulate region, the bilateral medial frontal gyrus, the thalamus and the insula.
Grey matter Conclusion: Our results suggest that brain regions in the reward network may be specifically related to PNS, es-
Persistent negative symptoms pecially the left caudate nucleus. It is possible that abnormality in reward processing may constitute the neural
Schizophrenia basis of PNS.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction levels of positive symptoms, depression and extrapyramidal side effects

Negative symptoms are core clinical features of schizophrenia and
contribute to deficits in cognitive and executive function (Bagney et
al., 2013; Bow-Thomas et al., 1999; Capleton, 1996). They are often per-
sistent in the whole course of schizophrenia in a large number of pa-
tients and are resistant to treatment (Kirkpatrick and Fischer, 2006;
Stahl and Buckley, 2007; Tandon et al., 2010). Increasing evidence has
suggested that negative symptoms include at least two dimensions,
namely the motivational dimension (e.g., anhedonia, avolition and
asociality) and the diminished expressivity dimension (e.g., restricted
affect and alogia) (Blanchard and Cohen, 2006; Kirkpatrick and
Fischer, 2006; Strauss et al., 2012). In particular, diminished pleasure
and motivation, which contribute to poor outcome, have been sug-
gested to be key aspects of negative symptoms (Barch and Dowd, 2010).
For research purposes, there are currently two main ways to concep-
tualize negative symptoms. The first way is the deficit syndrome (DS),
which includes only primary and enduring negative symptoms
(Carpenter et al., 1988). The second way is the concept of persistent
negative symptoms (PNS), which requires at least moderate severity
of negative symptoms for at least six months with defined threshold
⁎ Corresponding author at: Institute of Psychology, Chinese Academy of Sciences, 16
Lincui Road, Beijing 100101, China.
E-mail address: rckchan@psych.ac.cn (R.C.K. Chan).
during the stable phase of schizophrenia (Buchanan, 2007). The concept
of PNS shares three features with the DS, namely persistence, resistance
to treatment (Kalisz and Cechnicki, 2016), and the fact that both con-
structs include primary and enduring negative symptoms (Mucci et
al., 2016). However, compared with the DS, the PNS concept is more in-
clusive and consequently patients with PNS are easier to identify for re-
search purposes. Indeed, the PNS concept has been recognized by a
National Institute of Mental Health consensus statement in 2006
(Kirkpatrick et al., 2006), and a large number of studies have examined
the assessment, identification and treatment of PNS (Benoit et al., 2012;
Bodnar et al., 2014; Buchanan et al., 2015; Chue and Lalonde, 2014;
Hovington et al., 2015; Hovington et al., 2012; Mucci et al., 2016; Ucok
and Ergul, 2014).
Although many previous studies have identified a correlation be-
tween negative symptoms and grey matter reduction (Andreasen,
1989; Berman et al., 1988; Bishop et al., 1983; Johnstone et al., 1994;
Keilp et al., 1988; Luchins et al., 1984; Pfefferbaum et al., 1988; Saijo et
al., 2001), few studies have been carried out in schizophrenia patients
with PNS (Hovington and Lepage, 2012). Furthermore, results from
the few neuroimaging studies using the PNS construct are inconsistent
due to different imaging methods, terminologies, and under-powered
samples. Until recently, only three imaging studies have used the PNS
construct to investigate grey matter and white matter changes, but
they are all limited by small sample sizes (Benoit et al., 2012; Bodnar

http://dx.doi.org/10.1016/j.schres.2017.04.005
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10 Y. Li et al. / Schizophrenia Research 192 (2018) 9–15
et al., 2014; Hovington et al., 2015). A systematic narrative review on
the neuroanatomical correlates of PNS reported that structural deficits
of the frontal lobe and the temporal lobe may be specifically related to
PNS (Hovington and Lepage, 2012). More research is clearly needed to
explore the brain structural deficits of schizophrenia patients with
PNS with a larger sample size.
In this study, we aimed to quantitatively examine grey matter reduc-
tion in schizophrenia patients with PNS using Activation Likelihood Es-
timation (ALE) meta-analysis.
2. Methods
2.1. Study selection
We used the following key words to search for relevant studies in
online databases including PubMed, Web of Knowledge, Elsevier and
PsycINFO: schizophrenia, MRI, structural, negative symptoms, persistent
negative symptoms, grey matter. We included papers published in
these databases up to August 31, 2016.
Before Buchanan developed the criteria of PNS, many researchers
have used different criteria to identify patients with PNS (Bottlender
et al., 2003; Edwards et al., 1999; Malla et al., 2004). As a result, the
search was complicated by the use of different definitions, terminolo-
gies (e.g. “enduring negative symptoms”, “residual negative symptoms”
or “negative schizophrenia”) and assessment instruments. To address
this problem, we adopted the following inclusion and exclusion criteria
developed by Hovington and Lepage (2012) to identify the relevant
studies.
2.1.1. Inclusion criteria
(1) Negative symptoms must be measured by a validated negative
symptom scale, such as the Positive and Negative Syndrome
Scale (PANSS) and the Scale for the Assessment of Negative
Symptoms (SANS) and must reach at least mild or moderate se-
verity. Moreover, according to Buchanan's definition of PNS
(Buchanan, 2007), he pointed that it should define the positive
symptoms in low level. According to the criteria of PNS devel-
oped by Hovington and Lepage (2012), there were no criteria
on positive symptoms. Thus, we added more criteria on presence
of positive symptoms for the present study (see Fig. 1).
(2) The duration of illness (DOI) must be longer than or equal to six
months. According to the criteria of PNS, negative symptoms
must persist for a minimum of six months in a clinically stable
period (Buchanan, 2007). However, when we identified studies
on PNS, we found that most studies only reported the DOI rather
than the duration of negative symptoms. The reason for defining
a DOI of at least six months in this study was to ensure that first
episode schizophrenia patients whose clinical symptoms (espe-
cially positive symptoms) have not been stabilized would not
be inadvertently included.
2.1.2. Exclusion criteria
(1) Duplicated studies;
(2) Unrelated studies based on content and method;
(3) Studies investigating participants without at least mild to moder-
ate levels of negative symptoms, and without using a validated
negative symptom scale;
(4) DOI not reported or mean DOI of less than six months;
(5) Studies that did not use standardized space of Montreal Neuro-
logical Institute (MNI) or Talairach space, or contrast studies;
(6) A mean PANSS negative subscale score of b19, or a mean SANS
total score of b 20;
(7) A mean PANSS positive subscale score of N21, or a mean SAPS
total score of N20;
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(8) Studies in which the mean positive symptom scores of partici-
pants exceeded the mean negative symptom scores.
A total of 12 studies fulfilling the inclusion criterion of the PNS group
were included (see Table 1). A total of 556 patients with schizophrenia
and 765 normal controls were included in this meta-analysis. The low-
est mean PANSS negative subscale score was 19.8. The mean levels of
positive symptoms were all lower than negative symptoms in all 12
studies. Two of the studies reported grey matter concentration and 10
studies reported grey matter volume. Information on antipsychotic dos-
age of each study are also presented in Table 1.
2.2. Activation Likelihood Estimation
The Ginger ALE software was used for the present meta-analysis
(Laird et al., 2005). The ALE analyses were conducted in Talairach
space, and Lancaster transform was used if coordinates were reported
in MNI space originally (Lancaster et al., 2007). The Lancaster's method
was also used when Brett's formulation (Brett, 1999) was used for con-
version from MNI space to Talairach space. The ALE analysis on patients
with PNS included 12 studies (208 foci). We followed the recommenda-
tions of the Ginger ALE software (Laird et al., 2005) to obtain the final
clusters identified in both meta-analyses by controlling for the false dis-
covery rate (FDR) at p b 0.05 with a cluster extent threshold of
100 voxels.
3. Results
In the ALE analysis involving patients with PNS, the results showed
that there was significantly reduced grey matter volume at the bilateral
medial frontal gyrus (Brodmann area [BA] 11/10), the left precentral
gyrus (BA44), the left middle frontal gyrus (BA9), the left caudate nucle-
us (caudate head), the bilateral parahippocampal gyri, the left anterior
cingulate (BA32), the thalamus and the insula. More details see
Table 2 and Fig. 2.
4. Discussion
The present meta-analysis demonstrated that schizophrenia pa-
tients with PNS had significant grey matter volume reduction at the
left caudate nucleus, the left precentral region, the left middle frontal re-
gion, the bilateral parahippocampal region, the left anterior cingulate
gyrus, the bilateral medial frontal gyri, the thalamus and the insula.
This study is one of the few systematic reviews that quantitatively ex-
amines grey matter volume reduction in schizophrenia patients with
PNS.
Numerous studies have reported the relationship between grey
matter volume reduction and negative symptoms (Andreasen, 1989;
Berman et al., 1988; Bishop et al., 1983; Johnstone et al., 1994; Keilp et
al., 1988; Luchins et al., 1984; Pfefferbaum et al., 1988; Saijo et al.,
2001). Grey matter volume reduction in the prefrontal cortex (including
the orbitofrontal cortex and the medial and lateral prefrontal cortices)
have been consistently correlated with the severity of negative symp-
toms in numerous imaging studies (Baare et al., 1999; Hazlett et al.,
2008; Hirayasu et al., 2001; Koutsouleris et al., 2008). Taken together
with our findings, grey matter volume reduction in the prefrontal cortex
appears to be specifically correlated with PNS. Apart from the prefrontal
cortex, subcortical regions such as the caudate nucleus (Young et al.,
1991) and limbic regions (Koutsouleris et al., 2008), have also shown
grey matter volume reduction in schizophrenia patients with negative
symptoms. For example, consistent with our results, parahippocampal
grey matter was found to be significantly correlated with the severity
of negative symptoms in patients with PNS (Benoit et al., 2012;
Bodnar et al., 2014). However, increased grey matter volume in the
orbitofrontal cortex and the caudate nucleus has also been reported
 Y. Li et al. / Schizophrenia Research 192 (2018) 9–15 11

(Crespo-Facorro et al., 2007; Lacerda et al., 2007). These inconsistent re- According to the two-factor model of negative symptoms
sults may be attributed to variable terminologies and criteria in defining (Blanchard and Cohen, 2006), diminished pleasure (anhedonia) and
PNS as well as the influence of antipsychotic medications on the amotivation are key aspects of negative symptoms that are associated
mesolimbic dopamine system. with poor outcome in schizophrenia (Barch and Dowd, 2010). It has

Fig. 1. Flow chart depicting the article selection process.

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12 Y. Li et al. / Schizophrenia Research 192 (2018) 9–15

Table 1
Summary of articles included in ALE meta-analysis of PNS group.

NO. Study NS scale NS PS CPZ-eq (Mg/d) DOI (SCZ vs HC) Coordinates Grey matter measure

1 (Paillere-Martinot et al., 2001) PANSS 27.6 (7.7) 17.3 (5.3) 260 (190) 10 (7) years 20 vs 20 Talairach GMV
2 (Sigmundsson et al., 2001) PANSS 25 (5.9) 14.7 (4.8) — 13.9 (6.6) years 27 vs 27 Talairach GMV
3 (Kawasaki et al., 2004) SANS 10.3 (5) (0–25) 5.6 (4.6) 8.1 (8.0) (Hal-eq) 3.1 (3.1) years 25 vs 50 Talairach GMC
4 (Salgado-Pineda et al., 2004) SANS 21.21 (-) 9.78 (—) — 1 year 14 vs 14 Talairach GMV
5 (Jayakumar et al., 2005) PANSS 23 (7) 19 (8) — 10.3 (5.1) months 18 vs 18 Talairach GMV
6 (Kawasaki et al., 2007) SANS 11.6 (4.4) (0–25) 6.7 (4.6) 12.1 (7.4) (Hal-eq) 4.0 (4.7) years 16 vs 16 Talairach GMC
7 (Bassitt et al., 2007) PANSS 19.8 (6.7) 12.9 (4.7) — 14.4 (7.4) years 50 vs 30 Talairach GMV
8 (Koutsouleris et al., 2008) PANSS 22.3 (9.8) 19.0 (7.8) 316.7 (351.5) 1.6 (-) years 175 vs 177 MNI GMV
9 (Meisenzahl et al., 2008) PANSS 25.1 (8.9) 17.9 (8.5) 288.2 (338.3) 114.4 (113.1) ms 72 vs 177 MNI GMD
10 (Schuster et al., 2012) PANSS 25.7 (8.0) 20.0 (8.7) 187.2 (192.8) 29.2 (9.6) years 27 vs 40 Talairach GMV
11 (Bodnar et al., 2012) SANS 30.1 (15.4) 16.4 (13.9) 107.8 (61.4) 409.6 (283.5) weeks 16 vs 60 MNI GMV
12 (Poletti et al., 2016) PANSS 20.41 (4.55) 17.6 (5.98) 347.91 (198.69) 12.61 (8.68) years 96 vs 136 MNI GMV

Note: NS, negative symptoms; DOI, duration of illness; SCZ, schizophrenia; HC, healthy control; GMV, grey matter volume; GMC, grey matter concentration; GMD, grey matter density.
PANSS, Positive and Negative Syndrome Scale; SANS, Scale for the Assessment of Negative Symptom; MNI, Montreal Neurological Institute; PS: positive symptoms; CPZ: chlorpromazine;
Hal: haloperidol.

been postulated that negative symptoms, especially anhedonia and
amotivation, may be associated with problems in reward processing in
schizophrenia (Barch and Dowd, 2010; Gold et al., 2013; Hartmann et
al., 2015; Strauss et al., 2014). Berridge and Robinson (2003) have put
forward a model on reward, which divides reward processing into
three parts, namely “liking”, which refers to consummatory pleasure;
“wanting”, which links motivation with anticipatory pleasure; and
“learning”, which integrates stimuli and responses by utilizing associa-
tive conditioning and conscious memory(Berridge and Robinson,
2003). Dysfunction of any of the three components, which work and in-
teract with each other, may lead to anhedonia and amotivation in
schizophrenia.
The cortico-striatal circuit is a main part of the reward network,
which includes several brain regions, such as the ventral striatum, the
anterior cingulate cortex (ACC), the orbitofrontal cortex (OFC) and the
dorsolateral prefrontal cortex (DLPFC). It is important to note that
most of the regions in the reward network were found to have signifi-
cant grey matter volume reduction in the present study. These brain re-
gions are related to different components of reward processing, which
may be the neural basis of anhedonia and amotivation (Haber, 2011).
For example, the OFC plays an important role in integrating sensory in-
formation to update and maintain reward values. The information is
then projected to the ACC, which computes the effort in relation to the
reward value and relays the information to the DLPFC. The ultimate de-
cision-making process is made based on reward value, effort, and rein-
forcement memory. Our findings of grey matter volume reduction in
brain regions which are components of the reward network support
the hypothesis that dysfunction of the reward network may be the neu-
ral basis of negative symptoms in schizophrenia.
Another key observation in this study is grey matter volume reduc-
tion in the left caudate nucleus. Grey matter volume reduction in the
caudate nucleus has been consistently associated with negative symp-
toms (Bruen et al., 2008; Buchanan et al., 1993; Young et al., 1991).
However, the nucleus accumbens, the main part of the ventral striatum,
which has been regarded to have a significant role in the reward net-
work and reinforcement learning, was not found to have grey matter
volume reduction in this study. This may be due to the small sample
of studies included in this meta-analysis. Since the nucleus accumbens
is clearly an important part of the reward network, more studies are
needed to clarify this issue.
Our results also showed grey matter reduction in the bilateral
parahippocampal gyri. Recently, grey matter volume reduction in
the parahippocampal gyrus has been found to be correlated specifi-
cally with PNS (Benoit et al., 2012; Bodnar et al., 2014). The
parahippocampal gyrus plays an important role in memory
encoding. Interestingly, according to a previous review on PNS
(Hovington and Lepage, 2012), impairment in verbal memory
was found to be correlated with PNS. According to the model put for-
ward by Kring and Barch on pleasure and motivation, the building of
anticipatory pleasure is based on the memory of previous pleasure
experiences and information related to the maintenance and retriev-
al of pleasure (Kring and Barch, 2014). It is possible that grey matter
volume reduction of the parahippocampal gyrus may disturb this
process and lead to negative symptoms.
Grey matter volume reduction in the precentral gyrus was also ob-
served in this study. Although few studies have reported a relationship
between the volume of the precentral gyrus and negative symptoms, a
previous study by our group has found that cortical thickness of the
precentral gyrus is correlated with self-reported scores of anhedonia
in healthy volunteers (Wang et al., 2016).
Grey matter volume reduction in the insula cortex and the thalamus
were also found in the present study. A recent study on dysfunctional
insular connectivity has shown that the functional connectivity be-
tween the insula and the ACC during reward prediction is significantly
reduced in patients with first episode psychosis compared with healthy
controls (Schmidt et al., 2016). On the other hand, the thalamus has
multiple functions and is regarded as an information hub in the brain.
It is believed that the thalamus is the critical node in fronto-basal-gan-
glia circuitry, which has been associated with the reward network and
negative symptoms (Marchand et al., 2012). Further research is needed
to clarify the role of those regions in negative symptoms.
This study has three main limitations. First, although we identified
relevant studies using a stringent set of criteria in defining PNS, some
of studies included did not fully meet the criteria of PNS as proposed
by Buchanan (2007) due to variable terminologies and definitions of
PNS. Secondly, the clusters found in our study were contributed by
only a small number of studies; a larger sample size is needed. Thirdly,
several factors (e.g. antipsychotic medications, age and duration of neg-
ative symptoms) might have introduced heterogeneity in the included
studies. However, we were unable to find an appropriate method to
control these factors. We acknowledge that factors such as the stage of
illness (Glahn et al., 2008), antipsychotic medication (Fusar-Poli et al.,
2013), and ageing (DeLisi, 1997), could cause brain structural changes
and introduced bias to our results.
In conclusion, our findings support the hypothesis that negative
symptoms, especially anhedonia and amotivation, may derive from dys-
function of the reward network. Evidence of deficits in hedonic and mo-
tivational capacity may help to elucidate the underlying mechanism of
PNS in schizophrenia.
Role of funding source
The funding agents had no further role in the study design; in the collection, analysis
and interpretation of the data; in the writing of the manuscript; and in the decision to sub-
mit the paper for publication.

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 Y. Li et al. / Schizophrenia Research 192 (2018) 9–15 13

Fig. 2. Results from the Activation Likelihood Estimation meta-analysis of 12 voxel-based morphometric studies of the PNS group. Grey matter reduction in patients with schizophrenia
compared with healthy controls, displayed on a three-dimensional rendered brain. Significance threshold with a false discovery rate at p b 0.05.

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14 Y. Li et al. / Schizophrenia Research 192 (2018) 9–15

Table 2
Results of ALE analyses on grey matter reduction in schizophrenia with PNS.

Cluster # Volume (mm3) Peak ALE value Talairach coordinates (x, y, z) Brain regions

1 1328 0.024168666 −4 6 −2 (L) Caudate (caudate head)

2 1288 0.0183939 −42 4 10 (L) Precentral gyrus (BA44)
3 1080 0.02040745 −50 16 30 (L) Middle frontal gyrus (BA9)
4 936 0.021693088 −20 −10 −14 (L) Parahippocampal gyrus
5 752 0.020128375 4 36 −14 (L) Medial frontal gyrus (BA11)
0.015158731 −2 36 −14 (L) Medial frontal gyrus (BA11)
0.013287913 −8 36 −14 (L) Medial frontal gyrus (BA11)
6 608 0.02022016 18 −4 −16 (R) Parahippocampal gyrus
7 600 0.021930853 −6 42 2 (L) Anterior cingulate (BA32)
8 560 0.017341234 0 −12 8 (L) Thalamus
9 528 0.014930071 −42 12 −2 (L) Insula (BA13)
10 424 0.015664393 8 50 10 (L) Medial frontal gyrus (BA10)
11 384 0.017696839 40 14 0 (R) Insula
12 384 0.015092294 −6 −54 −12 (L) Medial frontal gyrus (BA10)
13 360 0.017817374 −16 38 −4 (L) Parahippocampal gyrus (BA30)
14 352 0.019263374 24 −58 −22 (R) Culmen
15 296 0.015815578 32 18 8 (R) Insula (BA13)
16 288 0.015043026 −34 −42 −20 (L) Culmen
17 240 0.015083228 22 52 14 (R) Middle frontal gyrus (BA10)
18 176 0.013148344 8 52 32 (R) Superior frontal gyrus (BA9)
19 144 0.01192474 −64 −14 20 (L) Postcentral gyrus (BA43)
20 120 0.012540283 −60 −24 24 (L) Inferior parietal lobule (BA40)
21 120 0.010814496 42 8 32 (R) Precentral gyrus (BA9)
0.010749155 42 4 36 (R) Precentral gyrus (BA9)
22 112 0.012188775 26 −20 −10 (R) Parahippocampal gyrus (BA28)
23 104 0.011523062 −32 −8 −30 (L) Uncus (BA20)

Note. ALE, Activation Likelihood Estimation; BA, Brodmann area; L: left; R: right.

Contributors
YL did the literature search, analyzed the data and wrote up the first draft of the man-
uscript. DJX, YW helped analyzed and interpreted the data. WXL and EFC commented the
manuscript significantly. RCKC generated the idea, interpreted the findings and
commented the manuscript significantly. All authors contributed to and have approved
the final text.
Conflict of interests
The authors declared that there are no conflicts of interest in relation to the subject of
this study.
Acknowledgement
This study was supported by a grant from the National Natural Science Fund China
(81571317), the Beijing Training Project for the Leading Talents in S & T
(Z151100000315020), the Beijing Municipal Science & Technology Commission Grant
(Z161100000216138), the “Strategic Priority Research Program (B)” of the Chinese Acad-
emy of Sciences (XDB02030002), the CAS Key Laboratory of Mental Health, Institute of
Psychology, and the CAS-SAFEA International Partnership Program for Creative Research
Teams (Y2CX131003).
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