Anterior cingulate volumes in schizophrenia: A systematic review and a meta-analysis of MRI studies

Schizophrenia Research 93 (2007) 1 – 12 www.elsevier.com/locate/schres

Anterior cingulate volumes in schizophrenia: A systematic review and a meta-analysis of MRI studies M. Baiano a,b , A. David c , A. Versace b,d , R. Churchill e , M. Balestrieri a,b , P. Brambilla a,b,f,⁎ a

d

Department of Pathology and Clinical and Experimental Medicine, Psychiatry Section, University of Udine, Italy b InterUniversity Center for Behavioural Neurosciences, University of Udine and University of Verona, Italy c Cognitive Neuropsychiatry Section, Institute of Psychiatry, King's College London, UK Department of Medicine and Public Health, Psychiatry and Clinical Psychology Section, University of Verona, Verona, Italy e Health Services Research Department, Institute of Psychiatry, King's College, London, UK f Scientific Institute ‘E. Medea’, Italy Received 7 April 2006; received in revised form 12 February 2007; accepted 16 February 2007 Available online 30 March 2007

Abstract Objectives: Several MRI studies have investigated the anterior cingulate in schizophrenia, as this is a key region for emotional processing and higher executive performances. A systematic review of structural MRI studies and a meta-analysis were conducted to explore whether anterior cingulate volumes are abnormal in patients with schizophrenia. Method: A systematic search strategy was used to identify eligible MRI studies. Thereafter, a meta-analysis was carried out by using a random effect model. Also, a meta-regression analysis was used to assess the influence of age, gender and slice thickness on effect sizes. Results: The meta-analysis was performed on seven studies. These results showed that the anterior cingulate volumes were significantly reduced in patients compared to healthy controls. Significant heterogeneity between these studies was observed. The meta-regression demonstrated that the effect size was significantly related only to slice thickness. Conclusions: Our work confirmed the presence of abnormally reduced anterior cingulate volumes in schizophrenia. However, several methodological issues limited the interpretation of these findings. Among these were different MR acquisition parameters and the small size of the sample, which was mostly composed of chronic patients. Future MRI studies should be planned to better understand the functional expression of anterior cingulate structural abnormalities. © 2007 Elsevier B.V. All rights reserved. Keywords: Anterior cingulate; Schizophrenia; Magnetic resonance imaging; Neuroimaging

1. Introduction

⁎ Corresponding author. Dipartimento di Patologia e Medicina Clinica e Sperimentale, Cattedra di Psichiatria, Policlinico Universitario, Via Colugna 50, 33100 Udine, Italy. Tel.: +39 0432 55 9494; fax: +39 0432 54 5526. E-mail address: [email protected] (P. Brambilla). 0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2007.02.012

The anterior cingulate gyrus is the frontal part of the cingulate cortex, which lies between the corpus callosum and the cingulate sulcus (Vogt et al., 2003), and is anatomically considered as an area of the prefrontal cortex. Specifically, it is a broad band of brain tissue covering the corpus callosum bilaterally on the sagittal

2

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

plane and including the Brodmann's areas 24, 25 and 33. The cingulate gyrus derives from the archicortical moiety (as well as hippocampus and dorsal prefrontal cortex) (Sanides, 1969), and is characterized by an intermediate level of neural differentiation (Yakolev, 1948). In fact, the anterior cingulate is part of the paralimbic cortex, which represents an intermediate stage of the phylogenetic development of the human brain, being cytostructurally similar to the neo-cortex (MacLean, 1990). In 1937, Papez observed that tumours pressing on the cingulate cortex caused loss of emotional spontaneity and affected thought and autonomic activities in humans (Papez, 1937), thus demonstrating for the first time that the anterior cingulate was crucial for emotional and cognitive modulation. To date, several studies have confirmed that this area is involved in the processing of emotional stimuli, expression of emotional behaviour, mood regulation, organization of higher cognitive functions (i.e. planning, problem solving and decision making) and autonomic response to emotional states (Gray et al., 2002; Teasdale et al., 1999). Recent neuroimaging reports suggest the existence of two interconnected functional regions within the cingulate cortex: (1) the rostral region (perigenual cingulate), strictly related to emotional processing, and (2) the caudal region, involved in cognitive and motor performance (Heckers et al., 2004). The anterior cingulate (Brodmann's areas 24, 25, 33) has extensive connections with other areas of the brain which are involved in emotional processing (Bush et al., 2002) such as the amygdala, the insula, the thalamus, the periacqueductal grey matter and the orbitofrontal cortex (Barbas, 2000; Lane et al., 1998). The Brodmann area 24 of the anterior cingulate (subgenual cingulate), located ventrally to the genu of corpus callosum, is also, potentially relevant to the pathophysiology of schizophrenia, as it participates in modulating decision making, planning and mood regulation (Vogt et al., 1995, 2003). Post-mortem studies reviewed by Keshavan and others (1994), have also shown decreased axonal connections, an altered number of specific neuronal populations, reduced neuronal density, and changes in neuronal somal size in the anterior cingulate cortex of patients suffering from schizophrenia (Benes et al., 1992; Benes, 1993, 1998). Furthermore, several structural magnetic resonance imaging (MRI) studies have found anterior cingulate volume reduction in patients with schizophrenia when compared to healthy controls. (Crespo-Facorro et al., 2000; Job et al., 2002; Kubicki et al., 2002; Salgado-Pineda et al., 2003; Shapleske et al., 2002; Sigmundsson et al., 2001; Yamasue et al., 2004). However, other controlled MRI studies have shown preserved anterior cingulate volumes in schizophrenia (Convit et al., 2001; Crespo-Facorro et al., 2000).

Therefore, findings are still somewhat controversial and no conclusive evidences on anterior cingulate atrophy in schizophrenia can be drawn. For this reason, the authors conducted a systematic review and a meta-analysis of structural MRI studies of absolute (grey plus white) anterior cingulate volumes in patients with schizophrenia to clarify whether or not this brain region is abnormally reduced. Additionally, specific methodological issues that might contribute to improving the design of future MRI investigations in this field are discussed. 2. Methods 2.1. Search strategy A systematic search strategy to find eligible studies for both the systematic review and meta-analysis was performed. All relevant documentation up to and including May 2006 was considered. Computer searches on MEDLINE (1966-May 2006), PSYCHINFO (1872May 2006), and EMBASE (1980-May 2006) databases were carried out. PUBMED, UK NATIONAL RESEARCH REGISTER and SIGLE (European Association of Grey Literature) databases were also explored. The following Medical Subject Heading categories were used: Magnetic Resonance Imaging (or MRI), schizophrenia, cingulate or gyrus cinguli, volume, morphology, morphometry and structure. A manual search of bibliographic cross-referencing complemented the search. 2.2. Inclusion/exclusion criteria for both the systematic review and meta-analysis Papers had to meet the following criteria to be included: 1) Investigation of anterior cingulate volumes in schizophrenia and comparison subjects. 2) Mean volumes reported. 3) Subjects between 15 and 65 year-old. 4) Patients with schizophrenia were diagnosed according to DSM-III, DSM-III-R, DSM-IV, ICD-9, ICD10 or other implicit or internal operational criteria. Samples comprising some schizoaffective subjects were considered for selection. 5) Published in English. Studies were excluded if: 1) Measurements referred to areas and not to volumes. 2) Voxel-based MRI methods or diffusion tensor imaging were used.

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

3) Non-schizophrenia psychosis or other schizophreniaspectrum disorders were studied. 4) Case reports or case series were described. In addition, in the studies which included the same subject population or part of it, only the publication with the largest sample size was selected. 2.2.1. Data extraction and quality rating Each paper was evaluated by two independent reviewers (M.B. and A.V.), and the following data from the article was used: age, gender, education, handedness, age at onset, duration of illness, number of hospitalizations, neuroimaging acquisition parameters (T1/T2, number of slices, slice thickness, angle of cut). Mean raw anterior cingulate and mean total brain (or intracranial content) volumes, volume correction and the methods used for statistical analysis were also extracted from the article. Furthermore, each study was rated for quality and completeness by the two independent reviewers using a 13-point check-list previously used by our group (Brambilla et al., 2003, 2004). This checklist was divided into three categories: subjects (items 1–4), methods for image acquisition and analysis (items 5–11) and results and conclusions (items 12, 13). The 13 specific items were: Category 1: subjects (1) patients were evaluated prospectively, specific diagnostic criteria were applied, and demographic data was reported; (2) healthy comparison subjects were evaluated prospectively, psychiatric and medical illnesses were excluded and demographic data was reported; (3) important variables (e.g. age, gender, intelligence quotient, i.e. IQ, handedness, socio-economic status, height or total brain measures) were checked, either by stratification or statistically; (4) sample size per group N 5. Category 2: methods for image acquisition and analysis (5) all neuroanatomic measurements were taken without considering group assignment or subject identity; (6) magnet strength N 1 T; (7) MRI slice-thickness ≤ 3 mm and more than 1 slice was identified and traced; (8) no gap width; (9) the imaging technique used was clearly described so that it could be reproduced;

3

(10) measurements were clearly described so that they could be reproduced; (11) inter-rater reliability N 0.90. Category 3: results and conclusions (12) statistical parameters for significant and important but not significant differences were provided; (13) conclusions were consistent with the results obtained and the limitations were discussed. Each item was scored 1, 0.5 or 0 if criteria were, fully met, partially met or unfulfilled, respectively. This numeric score was used to rate the completeness of published studies and not to criticize the investigators or the work itself. 2.3. Statistical analysis Meta-analyses were performed using STATA 8.0 (StataCorp LP, Texas). The standardized mean difference (SMD) or Cohen's d (Deeks et al., 1995) (which is the difference in the observed means divided by the pooled standard deviations of the samples) was calculated for the anterior cingulate volumes, as a measure of effect size. A random effect model was used to conduct the analysis (DerSimonian and Laird's method) (Deeks et al., 1995). This approach is more appropriate for studies with small sample sizes because it usually results in wider confidence intervals which reflect variability. It also assumes that the effect size for each study (θi) varies around the overall estimate following a normal distribution, with mean θ and variance τ2. A homogeneity statistic (Q) was also calculated in order to assess statistical heterogeneity between studies. Generally, if Q exceeds the upper tail critical value of chi-square on k − 1 degrees of freedom (df ), the observed variance is significantly greater than expected under the null hypothesis, i.e. no heterogeneity between different studies (H0: τ2 = 0). Consequently, the null hypothesis may be rejected. As we expected a significant result in the homogeneity test, a meta-regression analysis was planned to explore the effects of three potential sources of heterogeneity, by regressing effect size against slice thickness, gender and mean age. The random effects regression analysis was performed using the metareg command, available on STATA. A significance level of p b 0.05 was adopted. The standardized mean difference test was calculated to explore whether patients with schizophrenia and healthy control subjects differed significantly in anterior cingulate volumes, assuming that H0, standardized mean difference = 0, was the null hypothesis to reject.

4

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

3. Results 3.1. Systematic review A total of 327 references were identified. Respectively, 26 were taken from PSYCHINFO, 66 from PUBMED, 141 from EMBASE, 84 from OVID MEDLINE and OVID MEDLINE In process and other nonindexed citations, nine from SIGLE databases, and one from the UK NATIONAL RESEARCH REGISTER. Most of them (313) did not fit the inclusion criteria. Thus, 14 publications were finally selected. However, due to the considerable overlapping of samples in studies by Takahashi and others (Takahashi et al., 2002a: 40 patients and 40 controls; Takahashi et al., 2002b: 40 patients and 48 controls; Takahashi et al., 2003: 40 patients and 40 controls; Takahashi et al., 2004: 58 patients and 61 controls), only 11 publications were actually included in the systematic review (Choi et al., 2005; Crespo-Facorro et al., 2000; Goldstein et al., 1999, 2002; Haznedar et al., 2004; Hirayasu et al., 1999; Kopelman et al., 2005; Szeszko et al., 1999; Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005). The authors of the four publications mentioned above supplied three datasets, thus completing the data reported in the studies by Takahashi and others. Absolute (grey plus white) volumes for rostral, caudal and total anterior cingulate gyrus were described in full detail. Mean caudal and mean total (caudal plus rostral) volumes were calculated bilaterally in 88 subjects (40 schizophrenic patients, 48 healthy control subjects) while mean right and left rostral (perigenual) volumes were derived from 121 subjects (59 patients, 62 control subjects; in Takahashi et al., 2004). The dataset describing the largest sample size from the Takahashi et al. studies was chosen to be included in our meta-analysis. 3.1.1. Anterior cingulate and brain volumes Two of the 11 papers (Takahashi et al., 2004l; Zhou et al., 2005) reported on anterior cingulate grey and white matter, but not the absolute (grey plus white matter) volumes, while two studies reported on grey, but not white matter volumes (Crespo-Facorro et al., 2000; Yamasue et al., 2004). Nine out of the 11 studies explored right and left anterior cingulate separately. (Choi et al., 2005; Crespo-Facorro et al., 2000; Haznedar et al., 2004; Hirayasu et al., 1999; Kopelman et al., 2005; Szeszko et al., 1999; Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005). All of the studies, with the exception of one (Kopelman et al., 2005), showed standard deviations. Two reports investigated rostral and caudal anterior cingulate volumes (Choi et al., 2005; Crespo-Facorro

et al., 2000). Absolute and total (right plus left) anterior cingulate volumes were provided only by Goldstein and others (Goldstein et al., 1999. 2002). Three publications reported on the intracranial content volume (ICV) (Choi et al., 2005; Hirayasu et al., 1999; Takahashi et al., 2004), while five studies showed the whole brain (CrespoFacorro et al., 2000; Goldstein et al., 1999, 2002; Haznedar et al., 2004; Szeszko et al., 1999). One study described both ICV and whole brain volume (Yamasue et al., 2004). Two studies did not report on ICV or whole brain measures (Kopelman et al., 2005; Zhou et al., 2005). 3.1.2. Regions of interest and anatomic landmarks Region-of-interest (ROI) boundaries were described in full detail in six papers (Choi et al., 2005; Haznedar et al., 2004; Kopelman et al., 2005; Szeszko et al., 1999; Takahashi et al., 2004; Zhou et al., 2005). Two studies focused on anterior cingulate sub-regions, such as subgenual (Hirayasu et al., 1999) and perigenual (i.e. rostral) anterior cingulate (Takahashi et al., 2004). Perigenual cingulate landmarks were reported (Takahashi et al., 2004), but not those of subgenual cingulate (Hirayasu et al., 1999). Only one study considered the paracingulate gyrus as part of the anterior cingulate (Choi et al., 2005). 3.1.3. MRI methodology The 11 selected studies showed only slight differences in the imaging acquisition technique used. Indeed, all but one (Szeszko et al., 1999) used 1.5 T magnet strength, and seven out of 11 acquired images without gap between slices (Goldstein et al., 1999, 2002; Haznedar et al., 2004; Hirayasu et al., 1999; Szeszko et al., 1999; Takahashi et al., 2004; Zhou et al., 2005). Anterior cingulate volumes were traced using scans ≤ 3 mm in six studies (Choi et al., 2005; CrespoFacorro et al., 2000; Haznedar et al., 2004; Hirayasu et al., 1999; Takahashi et al., 2004; Zhou et al., 2005). Coronal (Crespo-Facorro et al., 2000; Goldstein et al., 1999, 2002; Hirayasu et al., 1999; Kopelman et al., 2005; Szeszko et al., 1999), sagittal (Choi et al., 2005; Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005) and axial (Haznedar et al., 2004) planes were used in reports six, four and one, respectively. Positional correction was described in five papers, while another five studies applied anterior cingulate volume correction, either for total brain size (Goldstein et al., 1999; 2002) or for ICV (Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005). See Table 1 for full details. 3.1.4. Clinical features of patient samples The mean age of the patients with schizophrenia was 33.7 ± 8.97 (min = 25.8; max = 44.9). They were out-

Table 1 Subject and methodological features of structural MRI studies investigating anterior cingulate volumes in schizophrenia Rf

Mean total AC volumes ± SD (cm3)

Mean total brain volumes or ICV ± SD (cm3)

Male:females/total subjects

Mean age ± SD (years)

Handedness

Slice thickness Acquisition plane

Positional correction

Volume correction

ICC or Inter RRÞ

IntraRR

11

Choi et al. (2005)

SCZ

HC

SCZ

HC

SCZ

HC

SCZ

HC

SCZ

HC

1.5 mm sagittal

Parallel to intercommissural line

No data

No data

No data

9.5

Crespo-Facorro et al. (2000)

No data SCZ

No data HC

1366.8 ± 131.3 SCZ

1361.8 ± 126.1 HC

15:7/22 SCZ

15:7/22 HC

26.6 ± 5.1 SCZ

26.2 ± 6.0 HC

All R SCZ

All R HC

1.5 mm coronal plane

Parallel to AC-PC line

No data

No data

No data

10

Goldstein et al. (1999)

No data 12.38 ± 3.7

No data 13.06 ± 2.7

1504 ± 103 1140.9 ± 116.9

1499 ± 119 1077.3 ± 97.4

26:0/26 17:12/29

34:0/34 12:14/26

26.4 ± 6.7 44.8 ± 10.5

25.2 ± 6.2 39.8 ± 11.5

21R:5L 23R:6L

32R:2L 22R:4L

3.1 mm coronal plane

No data

0.84

0.84

11

Goldstein et al. (2002) Haznedar et al. (2004) Hirayasu et al. (1999) Kopelman et al. (2005)

11.40 ± 2.5

12.19 ± 2.5

1082.9 ± 89.1

1073.1 ± 91.2

27:13/40

27:21/48

44.9 ± 10.2

40.5 ± 10.9

31R:9L

44R:4L

Internal criteria†

No data

No data

No data

No data

1271 ± 118

1317 ± 109

20:7/27

25:7/32

38.3 ± 14.3

41.8 ± 12.1

No data

No data

No data

No data

No data

1510 ± 101

1317 ± 109

14:3/17

18:2/20

27.2 ± 7.4

24.0 ± 4.3

All R

All R

No data

No data

No data

No data

No data

No data

No data

No data

30:0/30

30:0/30

33.5 ± 10.6

33.7 ± 7.9

All R

All R

3.1 mm coronal plane 1.2 mm axial plane 1.5 mm coronal plane 3 or 4 mm coronal plane

Parcellation unit volume/total cerebral volume Adjustment for cerebrum size No data

Parallel to the AC-PC line

No data

No data

Szeszko et al. (1999) Takahashi et al. (2004)

No data

No data

1264.6 ± 94.4

1315.3 ± 102.6

10:9/19

16:10/26

26.0 ± 5.15

29.1 ± 6.9

14R:5L

18R:8L

No data

No data

1485.1 ± 122.1

1493.4 ± 95.0

31:27/58

30:31/61

25.8 ± 4.8

24.5 ± 5.5

All R

All R

Unclear external landmarks No data

0.91

No data

3.1 mm coronal plane 1 mm sagittal plane

Not clearly described adjustment for ICV No data

0.92

0.92

12

Yamasue et al. (2004)

No data

No data

1220 ± 110

1260 ± 110

20:7/27

20:7/27

30.4 ± 7.9

30.0 ± 5.6

All R

All R

3 mm sagittal plane

No data

(Absolute AC volume/ ICV) x 100 Absolute ROI/ ICC)x 100

No data

No data

12.5

Zhou et al. (2005)

No data

No data

1550 ± 150 No data

1580 ± 160 No data

31:38/59

30:28/58

25.5 ± 4.9

24.8 ± 5.5

All R

All R

1.0 mm sagittal plane

Perpendicular to AC-PC line

100 x regional volume/ICV

0.93

No data

9.5 8.5 10

9 13

0.87

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

QR

QR: quality ratings; Rf: reference; AC = anterior cingulate; ICV = intracranial volumes; SD = standard deviation; ICC: intra-class correlation; IRR: inter-rater reliability; Intra RR: intra-rater reliability; SCZ: schizophrenia patients, HC: healthy controls; r = righthanded, L = left-handed; AC–PC: anterior commissure-posterior commissure; †: Use of midpoints of the decussations of the AC–PC and the midsagittal plane at the level of PC; § ICC related to total AC volumes.

5

6

Table 2 Voxel-based morphometry studies in schizophrenia showing significant abnormalities in the anterior cingulate cortex Study

Schizophrenia patients

Healthy controls

Magnetic Resonance Imaging (MRI) scanner

Software

Findings

Palliere-Martinot et al. (2001)

20 all males mean age: 29 ± 7.2 chronic

Bilateral GM and cWM reductions in the AC of SCZ patients

27: 26M/1F mean age: 34.9 ± 7.6

1.5 T General Electric (GE) Signa scanner 1.5 T GE Signa scanner

SPM96

Sigmundsson et al. (2001)

20 all males mean age: 26 ± 6 27: 25M/2F mean age: 32.2 ± 6.7

Significant deficits of GM volume were found in the AC gyrus.

Job et al. (2002)

34: 23/11 mean age: 21.35 ± 3.66 first-episode 16: 14M/2F mean age: 26 ± 7.5 first-episode 72 mean age: 34.1 ± 8.5 chronic

36: 17/19 mean age: 21.17 ± 2.37 18: 16M/2F mean age: 24.0 ± 4.5 32 mean age: 33.3 ± 8.7

1.0 T Siemens Magnetom scanner 1.5 T GE scanner

Nonstatistical parametric mapping registration and segmentation SPM99 SPM99

45: 23M/22F mean age: 26.4 ± 5.2 chronic 13: all males mean age:23.76 ± 5.65 firstepisode 35: 21M/14F mean age: 27.8 ± 6.2 25: 14M/11F mean age: 25.8 ± 4.5 early stage of illness 14: 7M/7F mean age: 25.05 ± 4.05 chronic 25: 18/7 mean age: 19.7 ± 5.05 first-episode

Five regions of lower GM concentration were found bilaterally in the AC gyrus of SCZ patients SCZ patients showed GM deficits inthe subgenual portion of the AC (BAs 24, 25), bilaterally widespread for hallucinators SCZ (41/72). The AC GM reduction observed bilaterally in all SCZ patients; it was greater in female SCZ. Local GM volumes were reduced in patients in right AC (BA 32)

14 unspecified M/F mean age: 25.14 ± 3.32 22: 13M/9F mean age: 20.4 ± 4

41: 32/12 mean age: 39.0 ± 5.6 25: 18/7F mean age: 37.3 ± 10.2

34: 17/17 mean age: 34.7 ± 7.2 52: 24/46 mean age: 39.3 ± 14.8

Narr et al. (2005)

72: 51M/21F mean age: 25.1 ± 4.7 first-episode

McIntosh et al. (2006)

26: 13M/13F mean age: 36.85 ± 13.7 47: 24M/23F mean age: 44.23 ± 12.69

Shapleske et al. (2002)

Suzuki et al. (2002) Salgado-Pineda et al. (2003)

Ha et al. (2004) Kawasaki et al. (2004)

Salgado-Pineda et al. (2004) Farrow et al. (2005)

Giuliani et al. (2005) McDonald et al. (2005)

Ohnishi et al. (2006)

1.5 T GE Signa Advantage MR system

SPM99

42: 22M/20F mean age: 26.1 ± 5.9 13: all males mean age: 23.36 ± 4.58

1.5 T Siemens Magnetom System 1.5 T GE Signa scanner

SPM96

35: matched mean age: 27.3 ± 6.7 50: 28M/22F mean age: 24.0 ± 5.7

1.5 T GE Signa scanner 1.5 T Siemens Magnetom Vision system 1.5 T GE Signa scanner

SPM99

SPM99

SPM99

SPM2

1.5 T Siemens Magnetron Vision Plus Magnetic Resonance system 1.5 T GE Signa scanner

SPM99

1.5 T GE N/Vi Signa System scanner

SPM99

78: 37M/41F mean age: 27.3 ± 6.6

1.5 T GE scanner

26: 14M/12F mean age: 34.12 ± 13.0

1.5 T GE scanner

Cortical pattern matching methods using 3D deformation field vector SPM99

76: 30M/46F mean age: 40.36 ± 11.92

1.5 T Siemens Magnetom Scanner

SPM: Statistical Parametric Mapping; GM: grey matter; WM: white matter; SCZ: schizophrenia; AC: anterior cingulate.

SPM2

SPM2

GM concentrations in bilateral AC were decreased in SCZ patients SCZ patients showed significant GM decrease in the AC cortex bilaterally Differences in local GM volumes were found in the right AC and left central cingulate of SCZ patients GM reductions were localized in the left AC gyrus of patients

SCZ males showed greater GM concentrations in the AC towards matched females GM deficits were predominant in the AC gyrus bilaterally in SCZ patients and were not differently expressed by SCZ males and SCZ females SCZ patients showed significant cortical thinning in AC; the effect was greater in left caudal AC for male SCZ and in the right cingulate for female SCZ GM reductions were observed in the AC (BA 32) of SCZ patients Reduced AC cortex volume in SCZ subjects (especially in left ACC for those homozygous for Val-COMT allele)

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

Kubicki et al. (2002)

GM reduced in the right AC of SCZ patients.

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

patients in two studies (Goldstein et al., 1999; 2002), inpatients in two reports (Choi et al., 2005; Kopelman et al., 2005) and both in-patients and out-patients in four publications (Hirayasu et al., 1999; Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005). Three studies did not clarify the source of recruitment of the subjects. (Crespo-Facorro et al., 2000; Haznedar et al., 2004; Szeszko et al., 1999). Five papers recruited chronic antipsychotic-treated patients (Goldstein et al., 1999, 2002; Takahashi et al., 2004; Yamasue et al., 2004; Zhou et al., 2005). Drug-naïve individuals at early stages of the illness (Crespo-Facorro et al., 2000) and first-episode patients (Hirayasu et al., 1999; Szeszko et al., 1999) were enrolled in three studies. One report investigated chronic patients, as well as firstepisode or early-onset individuals with schizophrenia (Kopelman et al., 2005). Two studies reported on drugfree or drug naïve patients, without clearly reporting the stage of their illness (Choi et al., 2005; Haznedar et al., 2004). To be more specific, in Choi and others (2005), 13 out of 22 patients were drug-naïve and nine out of 22 were drug free with a prior history of antipsychotic treatment, which was stopped four weeks before the scan (mean of total patients = 26.59 ± 5.1 years). In the study by Haznedar et al. (2004), seven out of 27 patients were neurolepticnaïve and the remaining 20 were drug-free for an average of 3 weeks (mean of total patients = 38.3± 14.3 years). All 11 studies excluded patients with a history of neurological disease, physical illness, and substance abuse. 3.1.5. Findings Reduced anterior cingulate volumes were found in patients with schizophrenia in nine out of the 11 studies. More specifically, lower absolute (grey plus white matter) anterior cingulate volumes were found in five reports in patients when compared to healthy control subjects (Choi et al., 2005, Goldstein et al., 1999, Goldstein et al., 2002; Haznedar et al., 2004, Hirayasu et al., 1999; Szeszko et al., 1999). Two publications showed reduced grey matter volumes (Crespo-Facorro et al., 2000; Yamasue et al., 2004) and another two studies found reduced volumes of both grey and white matter (Takahashi et al., 2004; Zhou et al., 2005) in people with schizophrenia. The remaining two studies reported on preserved bilateral grey matter (CrespoFacorro et al., 2000) and increased total absolute (Kopelman et al., 2005) anterior cingulate volumes in first-episode and chronic neuroleptic treated patients, respectively. Three out of the 11 studies explored gender stratification while the remaining eight studies did not specifically investigate gender effects. In fact, reduced right

7

archicortical volumes (comprising anterior cingulate and superior frontal gyri volumes) were found in male patients when compared to male control subjects (Szeszko et al., 1999). The effect of gender on anterior (Goldstein et al., 2002) and perigenual (Takahashi et al., 2004) cingulate volumes in the control sample (i.e. the fact that the volume is larger in females), was also not present in patients suffering from schizophrenia. 3.1.6. Study quality The mean quality score for the 11 reports was 10.4 (standard deviation: 1.80; minimum score: 7.5; maximum score: 13). The year of publication was correlated with the total quality score (r = 0.68) and with the study planning (r = 0.45), but not with the image acquisition technique used (r = 0.056). 3.1.7. Voxel-based morphometry, diffusion tensor, and magnetization transfer imaging studies Voxel-based morphometry (VBM), diffusion tensor imaging (DTI) or magnetization transfer imaging (MTI) studies in schizophrenia were also collected and described (Table 2 and 3). 46 voxel-based morphometry (VBM) papers were collected, of which 16 found reduced anterior cingulate grey matter in patients with schizophrenia when compared to control subjects (Table 2). Five investigated the whole cingulate gyrus without distinction between the anterior and the posterior portion; one reported on decreased grey matter volumes in the posterior cingulate, and 24 did not show any data involving the anterior cingulate or the whole cingulate gyrus. Novel approaches such as diffusion tensor imaging (DTI) or magnetization transfer imaging (MTI) have been used recently to obtain information on white matter abnormalities in schizophrenia. 13 papers reported on decreased fractional anisotropy (FA) of anterior cingulate or cingulate bundle in patients compared to healthy controls. Only one MTI study describing anterior cingulum abnormalities was identified and showed a bilaterally reduced magnetization transfer ratio in the anterior cingulate of patients (Table 3). 3.2. Meta-analysis Seven out of the 11 studies considered for the systematic review which showed absolute anterior cingulate volumes were also included in the meta-analysis, as the remaining four papers showed non homogenous data. Indeed, Crespo-Facorro et al. (2000) and Yamasue et al. (2004) described only grey matter volumes;

8

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

Table 3 Diffusion tensor imaging and magnetization transfer imaging studies investigating the anterior cingulate and the cingulate bundle in schizophrenia Study

Schizophrenia patients

Burns et al. (2003)

30, 15M/15F, 27/30 right-handed, mean age: 36.4 ± 11.2

Healthy controls

Methods

Findings

VBA

VBA/ROI analysis

No significant differences in FA were found in the right and left AC between patients and healthy controls AC bilaterally involved in MTRc reduction in patients

VBA

Lower FA in the right AC of patients

Voxel-wise correlation analysis VBA and ROI analysis

Negative correlation between FA and impulsiveness in the AC white matter

14, all males, all-righthanded median age: 34 ± 9.8 18 all males, all righthanded, mean age: 43 ± 5.9 26 matched for age, sex, handedness

VBM

No differences in terms of FA between patients and controls at the level of CB

VBA following a fixed segmentation thresholding LSDI protocol+ MTR maps

Patients showed smaller area and mean FA in the CB, bilaterally

34, 20M/14F, 33/34 right-handed, mean age: 15.4 ± 2.8

VBA

14 all right-handed,

ROI automatic mapping

Reduced left CB (connecting prefrontal and cingulate area)

VBA

Reduced left-higher-than-right FA asymmetry in the CB of schizophrenia patients The left cingulate showed increased ADC in schizophrenia patients

30, 15M/15F, 26/4 right-handed, mean age: 35.7 ± 12.4 Bagary et al. 30 first-episode subjects, 19M/11F, 27/ 30, 18M/12F, 28/30 (2003)† 30 right-handed, mean age: right-handed, mean 27.3 ± 7.4 age: 28.9 ± 5.5 Hao et al. 21 first-episode subjects, 12M/9F, all 21, 10M/11F, all right(2006) right-handed, mean age: 23.7 ± 5.5 handed, mean age: 25.1 ± 4.6 Hoptman et al. 25 all males, mean age: 38.6 ± 7.4 No controls (2004) Hubl et al. (2004)

Jones et al. (2006)

26 acute, all right-handed subjects : 13 with AH, 8M/5F; mean age: 33.3 ± 8.5 SD; 13 without AH, 8M/5F, mean age: 31 ± 9.3 SD 14, all males, all right-handed median age: 34 ± 9.3

Kubicki et al. (2003)

16 chronic subjects, all males, all right-handed, mean age: 43 ± 6.8

Kubicki et al. (2005)⁎

21 chronic subjects, all males, no detailed socio-demographic data

Kumra et al. (2005)

Nestor et al. (2004)

26 early-onset subjects, 8 schizoaffective patients, 14M/12F, 24/26 right-handed, mean age: 15.2 ± 2.2 14 chronic, all right-handed, mean age: 40.73 ± 7.17

Park et al. (2004)

23 all males, all right-handed; mean age: 44 ± 6.2

Shin et al. (2006) Sun et al. (2003) Wang et al. (2004)

13, 8M/5F, mean age: 32.0 ± 8.4

mean age: 41.94 ± 6.58 32 all males, all righthanded, mean age: 43 ± 7.2 19 chronic all right-handed subjects, 21 all right-handed, 11M/8F, mean age: 27.84 ± 4.78 11M/10F, mean age:27.09 ± 5.51 30, 18M/12F, all right handed, 19,12M/7F, all right mean age:27.4 ± 8.2 handed, mean age: 25.7 ± 8.2 21 all males, all-right-handed, mean 20 all males, all rightage: 29.24 ± 5.58 handed, mean age: 26.00 ± 5.99

VBA

ROI analysis

In the left CB, patients with AH had higher FA than patients without AH

FA was reduced bilaterally in the CB of patients; no changes of MTR in the anterior CB for patients, while changes were observed in the right posterior CB Patients showed a reduced FA in the left AC, in close proximity of the caudate nucleus

The anterior cingulum showed lower FA values in patients

ROI analysis Only the AC showed lower FA for both (AC and sides and reduced left-greater-than-right posterior cingulum) asymmetry in patients compared to healthy controls

VBA=voxel-based analysis; ROI=region-of-interest; FA =fractional anisotropy; AC=anterior cingulum; MTR=magnetization transfer ratio; AH =auditory hallucinations; CB=cingulate bundle; LSDI=line scan diffusion imaging; DTI=diffusion tensor imaging; MTI=magnetization transfer imaging.

Kopelman and others (2005) included means but not standard deviations and Zhou et al. (2005) investigated white and grey matter volumes separately. All of the seven publications, except for two (Choi et al., 2005; Takahashi et al., 2004) reported on grey and white matter separately.

First, a meta-analysis focusing on the total anterior cingulate volumes was performed. Although a slight overlap between the samples in Goldstein and others from the 1999 and 2002 version was detected, these papers were analysed separately, as a considerable number of

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

9

Fig. 1. Forest plot presenting the meta-analysis of bilateral anterior cingulate volumes in schizophrenia.

new subjects (11 patients and 22 control subjects) was added to the later study. The five studies reporting left and right anterior cingulate volumes were included by calculating the bilateral volumes (Choi et al., 2005; Haznedar et al., 2004; Hirayasu et al., 1999; Szeszko et al., 1999; Takahashi et al., 2004). The unadjusted volumes were used to calculate the corresponding effect sizes. Substantial heterogeneity emerged among these seven studies (Q = 17.28, df = 6, p = 0.008, τ2 = 0.1319) (Fig. 1). The overall estimate of standardized mean difference (SMD) in total anterior cingulate volumes between patients with schizophrenia and healthy control subjects was significant (z = 4.08, p b .001). A meta-regression analysis was conducted to explore potential sources of heterogeneity by regressing SMD against slice thickness, patient gender and age. This analysis showed a significant association with slice thickness (z = 4.07, p b .001) but not with the gender (z = 0.66, p = 0.509) or mean age of the patients (z = 1.95, p = 0.051). Then, the five studies that reported right and left anterior cingulate volumes separately were considered. Goldstein's studies were excluded, as they reported on mean total anterior cingulate volumes, but not bilateral volumes. No heterogeneity was detected (Q = 6.58, df = 4, p = 0.160, τ2 = 0.0506). The difference in the total anterior cingulate volumes between patients and healthy control subjects was confirmed by the SMD test (z = 5.65; p b .001); no significant heterogeneity for right or left anterior anterior cingulate volumes was found (Q = 1.85, df = 4, p = 0.763, τ2 b .001; Q = 2.28, df = 4, p = 0.685, τ2 b .001 respectively). Furthermore, right and

left anterior cingulate volumes appeared to be significantly smaller in patients compared to control subjects (z = 3.27, p = 0.001; z = 5.05, p b .001). Analysing the nine studies reporting ICV or whole brain volumes, no significant differences for these measures were found between patients and healthy controls (z = 0.66, p = 0.509) and no heterogeneity was found (Q = 11,67 df = 8, p = 0.167, τ2 = 0.0306). 4. Discussion 4.1. Systematic review The purpose of this paper was to explore whether absolute anterior cingulate volumes are reduced in patients with schizophrenia. The systematic review showed that nine out of the 11 included studies reported on an abnormal anterior cingulate volume reduction in patients, suggesting that this may be crucial for the structural anatomy of the disease. Furthermore, voxelbased morphometry and diffusion tensor imaging studies confirmed this finding, reporting anterior cingulate pathway alterations. However, the interpretation of these results is limited by several methodological issues and these should be taken into consideration. Firstly, individual morphological variability as well as different tracing approaches mean that this region of the brain was not traced in the same way in all studies. Higher resolution scans will be helpful in defining standard anatomical landmarks and also in improving segmentation

10

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

techniques. Secondly, most of the studies enrolled small samples from a variety of sources. The third point to consider is that all of the studies were cross-sectional, mostly investigating chronic patients. Therefore, large populations of high-risk subjects or untreated first-episode patients need to be longitudinally investigated to improve the statistical importance of the analysis (Pantelis et al., 2003). This could help to further understand whether anterior cingulate atrophy is present before the onset of the disease or is related to either the antipsychotic treatment or to the progression of the illness. Furthermore, it is important to detect specific morphological variations better (such as the presence of paracingulate gyrus). Moreover, patients with schizophrenia and healthy individuals should be well matched to minimize the effects of socio-demographic variables, such as age, gender, socio-economic status, handedness, height, weight and I.Q. Although the available MRI studies are limited by methodological constraints, the scores in the first column of Table 1, show that the quality of investigations in this field has improved over the recent years. In fact, the scores correlate with the year of publication and the adjustments in image acquisition. This suggests that high-quality techniques are vital in improving the ability to detect subtle brain volumes abnormalities in schizophrenia.

In conclusion, this systematic review and metaanalysis showed that total and bilateral anterior cingulate volumes are abnormally decreased in patients with schizophrenia. However, it is still unclear whether this is due more to abnormal brain development or neurodegeneration. Therefore, future MR studies should longitudinally investigate larger samples of high-risk individuals, drug-free first-episode patients and unaffected family members. Such populations are crucial to systematically examine whether anterior cingulate changes are already present before the appearance of symptoms, or whether they develop afterwards, as a result of the course of illness. Such MRI studies, together with cognitive and genetic investigations, are necessary to further investigate whether anterior cingulate atrophy represents an indicator of vulnerability to the disease and to better understand the functional expression of anterior cingulate structural abnormalities in schizophrenia. Acknowledgements This work was supported in part by grants to Dr. Brambilla from the American Psychiatric Institute for Research and Education (APIRE/AstraZeneca Young Minds in Psychiatry Award) and from the Italian Ministry of Education, University and Research (PRIN n. 2005068874).

4.2. Meta-analysis In the first part of the meta-analysis, total anterior cingulate volumes were shown to be abnormally reduced in patients with schizophrenia. However, considerable statistical heterogeneity was detected between studies, as shown in Fig. 1 (Choi et al., 2005; Haznedar et al., 2004; Hirayasu et al., 1999, Takahashi et al., 2004). In view of the small number of studies, it would be difficult to conclude that heterogeneity was dependent on half of them. Furthermore, all the confidence intervals overlapped with the pooled effect size, except that of Takahashi et al. (2004), suggesting that this study may influence the heterogeneity between the studies. The second part of the meta-analysis found that both right and left anterior cingulate gyri were significantly smaller in patients when compared to healthy control subjects. In fact, no heterogeneity was evident between the studies (Choi et al., 2005; Haznedar et al., 2004; Hirayasu et al., 1999; Szeszko et al., 1999; Takahashi et al., 2004). These findings are consistent with abnormally reduced anterior cingulate volumes in people with schizophrenia. However, the small number of meta-analysed studies could affect the application of the results to the general population.

References Bagary, M.S., Symms, M.R., Barker, G.J., Mutsatsa, S.H., Joyce, E.M., Ron, M.A., 2003. Gray and white matter brain abnormalities in first-episode schizophrenia inferred from magnetization transfer imaging. Arch. Gen. Psychiatry 60, 779–788. Barbas, H., 2000. Connections underlying the synthesis of cognitive, memory and emotion in primate prefrontal cortices. Brain Res. Bull. 52, 319–330. Benes, F.M., 1993. Neurobiological investigations in cingulate cortex of schizophrenic brain. Schizophr. Bull. 19, 537–549. Benes, F.M., 1998. Model generation and testing to probe neural circuitry in the cingulate cortex of postmortem schizophrenic brain. Schizophr. Bull. 24, 219–230. Benes, F.M., Vincent, S.L., Alsterberg, G., Bird, E.D., SanGiovanni, J.P., 1992. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J. Neurosci. 12, 924–929. Brambilla, P., Hardan, A.Y., Di Nemi, S.U., Perez, J., Soares, J.C., Barale, F., 2003. Brain anatomy and development in autism: review of structural MRI studies. Brain Res. Bull. 61, 557–569. Brambilla, P., Hardan, A.Y., Di Nemi, S.U., Caverzasi, E., Soares, J.C., Perez, J., Barale, F., 2004. The functional neuroanatomy of autism. Funct. Neurol. 19, 9–17. Burns, J., Job, D., Bastin, M.E., Whalley, H., Macgillivray, T., Johnstone, E.C., Lawrie, S.M., 2003. Structural disconnectivity in schizophrenia: a diffusion tensor magnetic resonance imaging study. Br. J. Psychiatry 182, 439–443.

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12 Bush, G., Vogt, B.A., Holmes, A., Dale, A.M., Greve, D., Jenike, M.A., Rosen, B.R., 2002. Dorsal anterior cingulate cortex: a role in rewardbased decision making. Proc. Natl. Acad. Sci. U. S. A. 99, 523–528. Choi, J.S., Kang, D.H., Kim, J.J., Ha, T.H., Roh, K.S., Youn, T., Kwon, J.S., 2005. Decreased caudal anterior cingulate gyrus volume and positive symptoms in schizophrenia. Psychiatry Res., Neuroimaging 139, 239–247. Convit, A., Wolf, O.T., De Leon, M.J., Patalinjug, M., Kandil, E., Caraos, C., Scherer, A., Saint-Louis, L.A., Cancro, R., 2001. Volumetric analysis of the pre-frontal regions: findings in aging and schizophrenia. Psychiatry Res. 107, 61–73. Crespo-Facorro, B., Kim, J.J., Andreasen, N.C., O'Leary, D.S., Magnotta, V., 2000. Regional frontal abnormalities in schizophrenia: a quantitative grey matter volume and cortical surface size study. Biol. Psychiatry 48, 110–119. Deeks, J.J., Altman, D.G., Bradburn, M.J., 1995. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger, M., Smith, G.D., Altman, D.G. (Eds.), Systematic Reviews in Health Care: Meta-analysis in Context. BMJ Publishing Group, London, pp. 290–299. Farrow, T.F.D., Whitford, T.J., Williams, L.M., Gomes, L., Harris, A.W.F., 2005. Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder. Biol. Psychiatry 58, 713–723. Giuliani, N.R., Calhoun, V.D., Pearlson, G.D., Francis, A., Buchanan, R.W., 2005. Voxel-based morphometry versus region of interest: a comparison of two methods for analysing gray matter differences in schizophrenia. Schizophr. Res. 74, 135–147. Goldstein, J.M., Goodman, J.M., Seidman, L.J., Kennedy, D.N., Makris, N., Lee, H., Caviness Jr., V.S., Faraone, S.V., Tsuang, M.T., 1999. Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging. Arch. Gen. Psychiatry 56, 537–547. Goldstein, J.M., Seidman, L.J., O'Brien, L.M., Horton, N.J., Kennedy, D.N., Makris, N., Caviness Jr., V.S., Faraone, S.V., Tsuang, M.T., 2002. Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch. Gen. Psychiatry 59, 154–164. Gray, J.A., Braver, T.S., Raichle, M.E., 2002. Integration of emotion and cognition in the lateral prefrontal cortex. Proc. Natl. Acad. Sci. U. S. A. 99, 4115–4120. Ha, T.H., Youn, T., Ha, K.S., Rho, K.S., Lee, J.M., Kim, I.Y., Kim, S.I., Kwon, J.S., 2004. Gray matter abnormalities in paranoid schizophrenia and their clinical correlations. Psychiatry Res., Neuroimaging 132, 251–260. Hao, Y., Liu, Z., Jiang, T., Gong, G., Liu, H., Tan, L., Kuang, F., Xu, L., Yi, Y., Zhang, Z., 2006. White matter integrity of whole brain is disrupted in first-episode schizophrenia. NeuroReport 17, 23–26. Haznedar, M.M., Buchsbaum, M.S., Hazlett, E.A., Shihabuddin, L., New, A., Siever, L.J., 2004. Cingulate gyrus volume and metabolism in the schizophrenia spectrum. Schizophr. Res. 71, 249–262. Heckers, S., Weiss, A.P., Deckersbach, T., Goff, D.C., Morecraft, R.J., Bush, G., 2004. Anterior cingulate cortex activation during cognitive interference in schizophrenia. Am. J. Psychiatry 161, 707–715. Hirayasu, Y., Shenton, M.E., Salisbury, D.F., Kwon, J.S., Wible, C.G., Fischer, I.A., Yurgelun-Todd, D., Zarate, C., Kikinis, R., Jolesz, F.A., McCarley, R.W., 1999. Subgenual cingulate cortex volume in firstepisode psychosis. Am. J. Psychiatry 156, 1091–1093. Hoptman, M.J., Ardekani, B.A., Butler, P.D., Nierenberg, J., Javitt, D.C., Lim, K.O., 2004. DTI and impulsivity in schizophrenia: a first voxelwise correlational analysis. NeuroReport 15, 2467–2470.

11

Hubl, D., Koenig, T., Strik, W., Federspiel, A., Kreis, R., Boesch, C., Maier, S.E., Schroth, G., Lovblad, K., Dierks, T., 2004. Pathways that makes voices. Arch. Gen. Psychiatry 61, 658–668. Job, D.E., Whalley, H.C., McConnell, S., Glabus, M., Johnstone, E.C., Lawrie, S.M., 2002. Structural gray matter differences between first-episode schizophrenics and normal controls using voxelbased morphometry. NeuroImage 17, 880–889. Jones, D.K., Catani, M., Pierpaoli, C., Reeves, S.J.C., Shergill, S.S., O'Sullivan, M., Golesworthy, P., McGuire, P., Horsfield, M.A., Simmons, A., Williams, S.C.R., Howard, R.J., 2006. Age effects on diffusion tensor magnetic resonance imaging tractography measures of frontal cortex connections in schizophrenia. Hum. Brain Mapp. 27, 230–238. Kawasaki, Y., Suzuki, M., Nohara, S., Hagino, H., Takahashi, T., Matsui, M., Yamashita, I., Chitns, X.A., McGuire, P.K., Seto, H., Kurachi, M., 2004. Structural brain differences in patients with schizophrenia and schizotypal disorder demonstrated by voxel-based morphometry. Eur. Arch. Psychiatry Clin. Neurosci. 254, 406–414. Keshavan, M.S., Anderson, S., Pettergrew, J.W., 1994. Is schizophrenia due to excessive synaptic pruning in the prefontal cortex? The Feinberg hypothesis revisited. J. Psychiatr. Res. 28, 239–265. Kopelman, A., Andreasen, N.C., Nopoulos, P., 2005. Morphology of the anterior cingulate gyrus in patients with schizophrenia: relationship to typical neuroleptic exposure. Am. J. Psychiatry 162, 1872–1878. Kubicki, M., Shenton, M.E., Salisbury, D.F., Hirayasu, Y., Kasai, K., Kikinis, R., Jolesz, F.A., McCarley, R.W., 2002. Voxel-based morphometric analysis of gray matter in first episode schizophrenia. NeuroImage 17, 1711–1719. Kubicki, M., Westin, C.F., Nestor, P.G., Wible, C.G., Frumin, M., Maier, S.E., Kikins, R., Jolesz, F.A., Mc Carley, R.W., Shenton, M.E., 2003. Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study. Biol. Psychiatry 54, 1171–1180. Kubicki, M., Park, H., Westin, C.F., Nestor, P.G., Mulkern, R.V., Maier, S.E., Niznikiewicz, M., Connor, E.E., Levitt, J.J., Frumin, M., Kikins, R., Jolesz, F.A., McCarley, R.W., Shenton, M.E., 2005. DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity. NeuroImage 26, 1109–1118. Kumra, S., Ashtari, M., Cervellione, K.L., Henderson, I., Kester, H., Roofeh, D., Wu, J., Clarke, T., Thaden, E., Kane, J.M., Rhinewine, J., Lencz, T., Diamond, A., Ardekani, B.A., Szeszko, P.R., 2005. White matter abnormalities in early-onset schizophrenia: a voxelbased diffusion tensor imaging study. J. Am. Acad. Child Adolesc. Psych. 44, 934–941. Lane, R.D., Reiman, E.M., Axelrod, B., Yun, L.S., Holmes, A., Schwartz, G.E., 1998. Neural correlates of levels of emotional awareness. Evidence of an interaction between emotion and attention in the anterior cingulate cortex. J. Cogn. Neurosci. 10, 525–535. MacLean, P.D., 1990. The Triune Brain. Plenum, New York. McDonald, C., Bullmore, E., Sham, P., Chitnis, X., Suckling, J., MacCabe, J., Walshe, M., Murray, R.M., 2005. Regional volume deviations of brain structure in schizophrenia and psychotic bipolar disorder. Br. J. Psychiatry 186, 369–377. McIntosh, A.M., Job, D.E., Moorhead, W.J., Harrison, L.K., Whalley, H.C., Johnstone, E.C., Lawrie, S.M., 2006. Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure. Am. J. Med. Genet. 141B, 76–83. Narr, K.L., Toga, A.W., Szeszko, P., Thompson, P.M., Woods, R.P., Robinson, D., Sevy, S., Wang, Y.P., Schrock, K., Bilder, R.M., 2005. Cortical thinning in cingulate and occipital cortices in first episode schizophrenia. Biol. Psychiatry 58, 32–40.

12

M. Baiano et al. / Schizophrenia Research 93 (2007) 1–12

Nestor, P.G., Kubicki, M., Gurrera, R.J., Niznikiewicz, M., Frumin, M., McCarley, R.W., Shenton, M.E., 2004. Neuropsychological correlates of diffusion tensor imaging in schizophrenia. Neuropsychology 4, 629–637. Ohnishi, T., Hashimoto, R., Mori, T., Nemoto, K., Moriguchi, Y., Iida, H., Noguci, H., Nakabayashi, T., Hori, H., Ohmori, M., Tsukue, R., Anami, K., Hirabayashi, N., Harada, S., Arima, K., Saitoh, O., Kunugi, H., 2006. The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. Brain 129, 399–410. Palliere-Martinot, M., Caclin, A., Artiges, E., Poline, J.B., Joliot, M., Mallet, L., Recasens, C., Attar-Levy, D., Martinot, J.L., 2001. Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia. Schizophr. Res. 50, 19–26. Pantelis, C., Velakoulis, D., McGorry, P.D., Wood, S.J., Suckling, J., Phillips, L.J., Yung, A.R., Bullmore, E.T., Brewer, W., Soulsby, B., Desmond, P., McGuire, P.K., 2003. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 361, 281–288. Papez, J.W., 1937. A proposed mechanism of emotion. Arch. Neurol. Psychiatry 38, 725–743. Park, H.J., Westin, C.F., Kubicki, M., Maier, S.E., Niznikievitz, M., Baer, A., Frumin, M., Kikins, R., Jolesz, F.A., McCarley, R.W., Shenton, M.E., 2004. White matter asymmetries in healthy subjects and in schizophrenia: a diffusion tensor MRI study. NeuroImage 23, 213–223. Salgado-Pineda, P., Baeza, I., Perez-Gomez, M., Vendrell, P., Junque, C., Bargallo, N., Bernardo, M., 2003. Sustained attention impairment correlates to gray matter decreases in first episode neuroleptic-naive schizophrenic patients. NeuroImage 19, 365–375. Salgado-Pineda, P., Junque, C., Vendrell, P., Baeza, I., Bargallo, N., Falcon, C., Bernardo, M., 2004. Decreased cerebral activation during CPT performance: structural and functional deficits in schizophrenic patients. NeuroImage 21, 840–847. Sanides, F., 1969. Comparative cytoarchitectonics of the neocortex of mammals and their evolutionary interpretation. Ann. N. Y. Acad. Sci. 167, 404–423. Shapleske, J., Rossell, S.L., Chitnis, X.A., Suckling, J., Simmons, A., Bullmore, E.T., Woodruff, P.W., David, A.S., 2002. A computational morphometric MRI study of schizophrenia: effects of hallucinations. Cereb. Cortex 12, 1331–1341. Shin, Y.W., Kwon, J.S., Ha, T.H., Park, H.J., Kim, D.J., Hong, S.B., Moon, W.J., Lee, J.M., Kim, I.Y., Kim, S.I., Chung, E.C., 2006. Increased water diffusivity in the frontal and temporal cortices of schizophrenic patients. NeuroImage 30, 1285–1291. Sigmundsson, T., Suckling, J., Maier, M., Williams, S., Bullmore, E., Greenwood, K., Fukuda, R., Ron, M., Toone, B., 2001. Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. Am. J. Psychiatry 158, 234–243. Sun, Z., Wang, F., Cui, L., Breeze, J., Du, X., Wang, X., Cong, Z., Zhang, H., Li, B., Hong, N., Zhang, D., 2003. Abnormal anterior cingulum in patients with schizophrenia: a diffusion tensor imaging study. NeuroReport 14, 1833–1836.

Suzuki, M., Nohara, S., Hagino, H., Kurokawa, K., Yotsutsuji, T., Kawasaki, Y., Takahashi, T., Matsui, M., Watanabe, N., Seto, H., Kurachi, M., 2002. Regional changes in brain gray and white matter in patients with schizophrenia demonstrated with voxelbased analysis of MRI. Schizophr. Res. 55, 41–54. Szeszko, P.R., Bilder, R.M., Lencz, T., Pollack, S., Alvir, J.M., Ashtari, M., Wu, H., Lieberman, J.A., 1999. Investigation of frontal lobe subregions in first-episode schizophrenia. Psychiatry Res. 90, 1–15. Takahashi, T., Kawasaki, Y., Kurokawa, K., Hagino, H., Nohara, S., Yamashita, I., Nakamura, K., Murata, M., Matsui, M., Suzuki, M., Seto, H., Kurachi, M., 2002a. Lack of normal structural asymmetry of the anterior cingulate gyrus in female patients with schizophrenia: a volumetric magnetic resonance imaging study. Schizophr. Res. 55, 69–81. Takahashi, T., Suzuki, M., Kawasaki, Y., Kurokawa, K., Hagino, H., Yamashita, I., Zhou, S.Y., Nohara, S., Nakamura, K., Seto, H., Kurachi, M., 2002b. Volumetric magnetic resonance imaging study of the anterior cingulate gyrus in schizotypal disorder. Eur. Arch. Psychiatry Clin. Neurosci. 252, 268–277. Takahashi, T., Suzuki, M., Kawasaki, Y., Hagino, H., Yamashita, I., Nohara, S., Nakamura, K., Seto, H., Kurachi, M., 2003. Perigenual cingulate gyrus volume in patients with schizophrenia: a magnetic resonance imaging study. Biol. Psychiatry 53, 593–600. Takahashi, T., Suzuki, M., Zhou, S.Y., Hagino, H., Kawasaki, Y., Yamashita, I., Nohara, S., Nakamura, K., Seto, H., Kurachi, M., 2004. Lack of normal gender differences of the perigenual cingulate gyrus in schizophrenia spectrum disorders. A magnetic resonance imaging study. Eur. Arch. Psychiatry Clin. Neurosci. 254, 273–280. Teasdale, J.D., Howard, R.J., Cox, S.G., Ha, Y., Brammer, M.J, Williams, S.C., Checkley, S.A., 1999. Functional MRI study of the cognitive generation of affect. Am. J. Psychiatry 156, 209–215. Vogt, B.A., Nimchinsky, E.A., Vogt, L.J., Hof, P.R., 1995. Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J. Comp. Neurol. 359, 490–506. Vogt, B.A., Berger, G.R., Derbyshire, S.W., 2003. Structural and functional dichotomy of human midcingulate cortex. Eur. J. Neurosci. 18, 3134–3144. Wang, F., Sun, Z., Cui, L., Du, X., Wang, X., Zhang, H., Cong, Z., Zhang, D., 2004. Anterior cingulum abnormalities in male patients with schizophrenia determined through diffusion tensor imaging. Am. J. Psychiatry 161, 573–575. Yakolev, P.I., 1948. Motility behaviour and the brain: stereodynamic organization and neural coordinates of behaviour. J. Nerv. Ment. Dis. 107, 313–335. Yamasue, H., Iwanami, A., Hirayasu, Y., Yamada, H., Abe, O., Kuroki, N., Fukuda, R., Tsujii, K., Aoki, S., Ohtomo, K., Kato, N., Kasai, K., 2004. Localized volume reduction in prefrontal, temporolimbic, and paralimbic regions in schizophrenia: an MRI parcellation study. Psychiatry Res. 131, 195–207. Zhou, S.Y., Suzuki, M., Hagino, H., Takahashi, T., Kawasaki, Y., Matsui, M., Seto, H., Kurachi, M., 2005. Volumetric analysis of sulci/gyri-defined in vivo frontal lobe regions in schizophrenia: precentral gyrus, ingulate gyrus, and prefrontal region. Psychiatry Res., Neuroimaging 139, 127–139.