Original Paper Received: May 16, 2013 Accepted after revision: November 2, 2013 Published online: January 22, 2014
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
Structural Abnormalities in Schizophrenia: Further Evidence on the Key Role of the Anterior Cingulate Cortex P. Salgado-Pineda a, b R. Landin-Romero a E. Fakra c, d P. Delaveau e B.L. Amann a, b O. Blin c
a
FIDMAG Hermanas Hospitalarias Research Foundation, Sant Boi de Llobregat and b CIBERSAM, Barcelona, Spain; CIC-UPCET, Hôpital de la Timone, INCM, UMR CNRS 6193 and d Pôle Universitaire de Psychiatrie, CHU Sainte-Marguerite, APHM, Marseille, and e Centre Emotion, CNRS USR 3246, Groupe Hospitalier Pitié Salpêtrière, Paris, France c
Key Words Schizophrenia · Cingulate gyrus · Structural magnetic resonance imaging
Abstract Objective: The present study examined whole-brain structural abnormalities in schizophrenia, with a special focus on the anterior and posterior cingulate cortex (ACC, PCC) as this is an understudied issue in schizophrenia. Method: Wholebrain voxel-based morphometry analyses of gray matter (GM) and white matter (WM) were performed to detect volumetric differences between 14 patients with schizophrenia and 14 healthy controls matched for age, sex, educational level and parents’ educational level. We examined withingroup GM and WM correlations and completed the analysis with measurements of sulci in medial cortical areas. Results: Compared with the healthy controls, the schizophrenic patients showed significant decreases in GM volumes in the ACC and PCC, and in neighboring WM regions such as the corpus callosum and the fimbriae of the fornix. Moreover, the patient group also displayed a negative correlation between volumes of GM and WM in the ACC. Finally, the patients showed significantly reduced volumes in the right cingulate sulci and left inferior frontal sulci. Conclusion: Our re-
© 2014 S. Karger AG, Basel 0302–282X/14/0691–0052$39.50/0 E-Mail [email protected] www.karger.com/nps
sults replicate typical brain-structural abnormalities with new findings in the medial prefrontal cortex, suggested to be a key region in this disorder. © 2014 S. Karger AG, Basel
Introduction
During the past 30 years, remarkable progress has been made in the identification of structural brain changes in schizophrenia. Hereby, schizophrenia is characterized by a reduction in whole volume of around 2%, coupled with larger reductions in regions such as the frontal lobe and the hippocampus [1, 2]. Ellison-Wright and Bullmore [3] meta-analyzed 42 voxel-based morphometry (VBM) studies on schizophrenia and found gray matter (GM) volume reductions in the frontal, temporal, cingulate and insular cortices and the thalamus. Some VBM studies in schizophrenia have described GM abnormalities as also affecting the adjacent white matter (WM) regions [4]. Cerebral abnormalities in the cingulate gyrus play a crucial role in the cognitive dysfunction and emotional disturbances that characterize schizophrenia. In brief, the cingulate gyrus is a cortical area of mixed cytoarchitecDr. Pilar Salgado-Pineda FIDMAG Hermanas Hospitalarias Research Foundation, FIBERSAM c/o Dr. Antoni Pujadas, 38 ES–08830 Sant Boi de Llobregat, Barcelona (Spain) E-Mail psalgado @ hospitalbenitomenni.org
tonics that links the limbic system and the neocortex. It is subdivided into two components, which are separated on the basis of cytoarchitecture, projection patterns and functions [5]: (1) the anterior cingulate cortex (ACC), which plays an important role in emotional, cognitive/attentional and nociceptive functioning as well as motor processing, and (2) the posterior cingulate cortex (PCC), which has a prominent role in pain and memory retrieval and, along with the precuneus, is implicated in human awareness [6]. In an extensive review of that topic, the authors suggest in brief that schizophrenia deficits involve the cingulate cortex and especially the ACC, with negative consequences on executive functioning, selective attention, error detection, word generation, working memory and the evaluation of the emotional significance of events [7]. They also highlight that the majority of neuroimaging studies in schizophrenia reported a reduction in ACC and PCC GM volumes and WM alterations in these regions, using diffusion tensor imaging (DTI) analysis. Some studies on schizophrenia have demonstrated reductions in the volumes of both the ACC [8–13] and the PCC [14, 15], but other groups found no significant differences between schizophrenic patients and controls [16, 17], or even a larger left ACC volume – correlated with neuroleptic exposure – in schizophrenic patients than in healthy controls [18]. A recent study also found diminished cortical thickness in the PCC in schizophrenic patients, which was correlated with altered WM connectivity [19]. In a multimodal study, using VBM functional magnetic resonance imaging (MRI) and DTI combined with tractography, Pomarol-Clotet et al. [20] have reported convergent structural and functional abnormalities in a specific medial frontal region corresponding to the anterior midline node of the so-called ‘default mode network’ (DMN). The DMN has been implicated in self-directed mental activity, specifically including episodic memory retrieval, inner speech, mental imagery, emotions and planning of future events [21–24]. There is increasing evidence of DMN abnormalities in schizophrenia, and most studies report that both structural and functional changes are maximal in the medial frontal area which overlaps the anterior midline node of this network [25]. Using an emotional face recognition task in a group of 14 patients with schizophrenia, we have recently also demonstrated that, compared with healthy controls, schizophrenic patients showed deactivation failures in both the anterior and the posterior midline nodes of the DMN that were strongly correlated with GM volume reductions in the same areas [26].
Table 1. Clinical and demographic data on schizophrenic patients
Cingulate Abnormalities in Schizophrenia
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
and healthy controls
Age, years Age range, years Gender – male/female, n Education level, years Parents’ educational level, years Duration of illness, years Total PANSS score Negative factor Positive factor Excitation factor Cognitive factor Depression factor
Control group (n = 14)
Patient group (n = 14)
34.64±5.96 23–48 9/5 14.23±2.05 12.21±3.31 – – – – – – –
37.29±8.87 22–56 9/5 12.2±4.22 13.08±4.42 14±6.70 60.7±12.0 13.14±5.46 24.71±8.42 8.43±2.47 7.93±3.32 6.5±2.74
Values denote means ± SD unless otherwise indicated. PANSS = Positive and Negative Syndrome Scale.
The purpose of the present study was to explore structural brain differences, using a whole-brain approach but focusing on the ACC, PCC and neighboring WM regions in order to provide complementary information on the structural abnormalities typically found in schizophrenia. Based on the previous literature, we hypothesized significantly smaller GM volumes in the posterior and anterior nodes of the DMN and neighboring WM regions. Furthermore, we predicted a replication of changes in global gyrification in our patient sample, as suggested by previous studies on schizophrenic patients [27]. More specifically, differences in local gyrification were hypothesized a priori in the anterior cingulate sulcus (ACS) and the posterior cingulate sulcus (PCS), bilaterally.
Methods Participants The patient sample consisted of 14 right-handed schizophrenic patients recruited from the Department of Psychiatry of Sainte Marguerite Hospital in Marseille, France. They all met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia, based on interviews and a review of the clinical history conducted by 2 psychiatrists. They all were scanned in a relatively stable clinical condition, based on scores on the Positive and Negative Syndrome Scale (table 1). All patients received neuroleptic medication, with 11 patients being treated with atypical antipsychotics (amisulpride, n = 3; risperidone, n = 3; olanzapine, n = 3; aripiprazole, n = 2) and 3 with atypical neuroleptics, in this case haloperidol.
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The controls consisted of 14 healthy subjects and they were matched for handedness, age, educational level and parental educational level. They had no history of psychiatric or neurological disease and no history of or current drug abuse or dependency. All participants in the current study were the same subjects from a previous multimodal study on schizophrenia [26]. The study was approved by the local ethics committee (Comité Consultatifs de Protection des Personnes se prêtant à des Recherches Biomédicales, Marseille). Each participant was registered in the French National File of Registrations and gave his/her written informed consent before entering the study. Neuroimaging Data Acquisition Three-dimensional anatomical images were acquired in a single MRI scanning session using a 3-Tesla scanner (Bruker, Ettlingen, Germany) at the functional MRI Center of Marseille, France. A set of high-resolution T1-weighted images was acquired using the following acquisition parameters: sagittal magnetization prepared rapid acquisition gradient echo sequence; TE/TR = 5/25 ms; TI = 800 ms; flip angle = 15°; and matrix = 256 × 256 × 128. Neuroimaging Data Analysis VBM Analysis The T1-weighted images were analyzed by the VBM technique using SPM5 software (Statistical Parametric Mapping; Wellcome Department of Cognitive Neurology, University College London, UK) implemented in Matlab 7.7.0 (Mathworks, Sherborn, Mass., USA). Briefly, VBM analysis is a comparison of tissue volumes between two groups of subjects [28]. The data have to be preprocessed by segmenting different tissue types and normalizing to the same anatomical space. Finally, a statistical parametric map shows regions where a concentration of a certain tissue type differs between groups. The data set was preprocessed using the unified segmentation approach [29] by estimating the model parameters for a maximum a posteriori solution alternating among classification, bias correction and registration steps in the same generative model. The registered images were then modulated to correct for regional expansion/shrinkage during spatial normalization. The data were spatially smoothed with an isotropic gaussian kernel of 12 mm of full-width half maximum. Statistical inference was made by wholebrain voxel-wise fitting of a general linear model, and statistical significance was corrected for multiple comparisons using the gaussian random field theory (RFT). Sulcus Measurement We used the Anatomist/BrainVISA 4.0 package (Neurosciences Cognitives et Imagerie Cérébrale, UPR 640-CNRS LENA) to identify and quantify the sulci. This software allows an automatic recognition of the main sulci of the human cortex. The representation nodes are cortical folds, which are given a sulcus name by a contextual pattern recognition method. The brain images were reoriented, segmented and processed following standard automatic methods contained in the BrainVISA software [30]. The first author (P.S.-P.) reviewed the results of the automated labeling and manually relabeled any incorrect sulci using the Atlas of the Cerebral Sulci [31]. For the purposes of the present study, we quantified the bilateral volumes (in cubic millimeters) of the ACS and PCS, the inferior frontal sulcus (IFS) and callosal sulcus (CS), bilaterally. Statistical analyses were per-
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Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
formed using the Statistical Package for the Social Sciences (SPSS Windows, version 12.0; SPSS Inc., Chicago, Ill., USA). Due to the small sample size, the data did not meet the assumption of a normal distribution (Shapiro-Wilk test; W statistic, p < 0.05). Therefore, we performed nonparametric analyses of variance between groups. Correlations between Volumes of GM and WM In order to assess the correlations between volumes of GM and WM in patients and controls, we performed a voxel-wise multimodal correlation using the biological parametric mapping (BPM) statistical toolbox [32]. The BPM toolbox incorporates information obtained from other modalities as regressors in a whole-brain voxel-wise analysis. The BPM toolbox uses the general linear model for statistical estimation, and RFT or false discovery rate (FDR) for statistical inference. We have used the implemented RFT-based inference for image correlation analysis, which is more appropriate in this context [32]. A threshold of p < 0.05 was used for all analyses.
Results
Demographic and Clinical Data The demographic and clinical data on the patient and control groups are shown in table 1. The groups were matched for handedness, age, educational level and parental educational level. There were no significant differences at p < 0.05 between the patients and controls in all demographic variables. Neuroimaging Results VBM Findings At an FDR-corrected p < 0.05, whole-brain differences in GM volume were localized medially, extending bilaterally from the anterior to the posterior cingulate gyrus (fig. 1). The patients showed reduced volumes compared with controls in the anterior (peak in Brodmann area, BA, 32; MNI coordinates: –12, 34, 17; z value = 4.49), central (peak in BA 24; MNI coordinates: –12, –15, 42; z value = 4.64) and posterior cingulate (peak in BA 30; MNI coordinates: 6, –46, 21; z value = 2.41), as well as in the medial frontal cortex (peaks in BA 9, MNI coordinates: –8, 42, 27, z value = 4.31, and in BA 11, z value = 4.22). These findings were basically a replication of those of from our previous study of GM reductions in patients with schizophrenia [26]. At an FDR-corrected p < 0.05, we found significant decreases in WM volume in the schizophrenia group compared with the controls in the corpus callosum and in the fimbriae of the fornix bilaterally (fig. 1). No increases in WM or GM were observed in our schizophrenia sample when compared with the controls. Salgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
Color version available online
Fig. 1. Decreases in GM (winter range) and WM (hot range; color online only) volumes in patients with schizo-
phrenia (n = 14) compared with healthy controls (n = 14).
Sulcus Measurements The descriptive values of the ACS, PCS, IFS and CS in each hemisphere for the two groups are summarized in table 2. The nonparametric analysis of variance revealed that, compared with the healthy subjects, the schizophrenic patients showed significantly reduced volumes in the right ACS (z = 3.033; p = 0.002) and left IFS (z = 2.205; p = 0.027). Correlations between Volumes of GM and WM A whole-brain analysis in the schizophrenia group yielded one cluster of significant negative correlation between the volumes of GM and WM in the ACC (BA 32; MNI coordinates: 2, 40, 19; Pearson’s correlation index = –0.82; p < 0.001). Although we did not find any cluster of significant correlation in the healthy controls, we decided to explore the relationship between GM and WM volumes and ACC cluster in healthy controls as well. Contrary to the patient group, we observed a positive tendency for a correlation Cingulate Abnormalities in Schizophrenia
between GM and WM only, without reaching statistical significance (Pearson’s correlation index = 0.45; p = 0.103; fig. 2).
Discussion
In the present study we replicated findings in schizophrenic patients, in comparison with healthy controls, of a structural abnormality in GM and WM that extended along the midline of the brain from the frontal to the occipital lobe. This pattern of structural abnormality involved several regions that have previously been reported on in the literature on structural abnormalities in schizophrenia, such as sections of the ACC and PCC and neighboring regions of the WM. However, some of our results, the negative correlation between GM and WM and decreased volumes of the sulci, were only limited to the ACC and are novel in the literature. Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
55
0.14
0.10
0.12
0.08
0.10 WM
WM
0.12
0.06 0.04
0.06
0.02
0.04
0
a
0.02 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 GM
Fig. 2. Scatter plot displaying within-group relationships between GM and WM in schizophrenic patients (a) and controls (b) in the
anterior cingulate gyrus (BA 32; MNI coordinates: 2, 40, 19). The patient group exhibited a significant negative correlation (Pear-
Table 2. Sulcus volumetric measurements in patient and control
groups
Right ACS Left ACS Right IFS Left IFS Right CS Left CS Right PCS Left PCS
Control group (n = 14) volume, mm3
Patient group (n = 14) volume, mm3
Between-group z
p1
780.15±568 742.65±178 1,118.50±152 1,064.73±465 491.03±381 504.16±291 875.95±273 728.58±230
326.40±229 649.33±282 961.15±340 737.48±357 380.09±269 391.93±274 678.96±316 597.48±171
3.033 0.965 0.191 2.205 0.322 1.103 1.608 1.608
0.002* 0.352 0.376 0.027* 0.769 0.285 0.114 0.114
Values denote means ± SD unless specified otherwise. * Significant statistical difference. 1 All p values FDR corrected.
Compared with the healthy controls, the schizophrenic patients showed decreased GM volumes localized medially and extending bilaterally from the anterior to the posterior cingulate gyrus. These volumetric cingulate abnormalities in schizophrenic patients are in agreement with the theory of aberrant maturation of the brain. A recent study by Supekar et al. [33] reported convergent structural and functional connectivity results, suggesting that the posterior cingulate-medial prefrontal connectivity along the cingulum bundle is the most immature link in the DMN of children compared with young adults. The authors proposed that the maturation of the PCC-medial 56
0.08
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
b
0.4
0.5
0.6
0.7
GM
0.8
0.9
1.0
1.1
son’s correlation index = –0.82; p < 0.001) between the volumes of WM and GM. The healthy controls presented a WM and GM relationship with a positive tendency that did not reach statistical significance (Pearson’s correlation index = 0.45; p = 0.103).
prefrontal cortex connectivity plays an important role in the development of self-related and sociocognitive functions that emerge during adolescence. An abnormal maturation of these brain networks could explain the social and cognitive impairment in schizophrenia, and a dysfunction of these regions could be essential in children at risk for the disorder. The schizophrenic patients of our study showed reduced WM volumes in the entire corpus callosum. Postmortem studies of the corpus callosum in schizophrenia have reported anatomical dysmorphology expressed as increased/decreased thickness, decreased cross-sectional area or decreased fiber density [34–36]. MRI studies have reported callosal abnormalities in schizophrenia, although results across studies have not always been in agreement (for a review, see [37]). In a recent meta-analysis, Arnone et al. [38] analyzed the data from 28 MRI studies assessing callosal volumes in schizophrenic patients compared with healthy subjects and confirmed the presence of reduced callosal areas in schizophrenia. DTI analyses have also reported abnormalities in the integrity of the corpus callosum in schizophrenia [39–42]. The patients of our study also showed reduced WM volumes in the fimbriae of the fornix bilaterally. The fimbria of the fornix is the main hippocampal output, one of the most frequently implicated brain structures, which has been consistently reported to be abnormal in schizophrenia [1, 37, 43–48]. Few studies have investigated the fornix in schizophrenia, reporting contradictory results. Zahajszky et al. [49] found no MRI volumetric differences between healthy controls and patients with chronic schizoSalgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
phrenia. In contrast, Davies et al. [50] showed an increase in volume in the cross-sectional area of the fornix in earlyonset schizophrenia. In the only post-mortem study evaluating the fornix, increased fiber densities in the left fornix of male subjects with schizophrenia were found [51]. Two recent DTI studies assessed WM integrity in the fornix in schizophrenia. One reported a decrease in fiber integrity in subjects with chronic schizophrenia compared with healthy controls [52], while the other found a bilateral disruption in fornix integrity in schizophrenia [53]. Together, our findings of reduced GM and WM volumes support the classic notion of a frontostriatal structural abnormality in schizophrenia. In this context, a recent multimodal voxel-wise meta-analysis of 79 studies revealed overlapping GM and WM structural findings in schizophrenia [4]. Among the regions, they especially highlighted alterations in limbic and subcortical structures, GM abnormalities in the bilateral prefrontal cortex and WM changes, including tracts that connect these structures within them and between hemispheres. The authors argue that these overlapping GM and WM abnormalities might be secondary to each other or represent a marker of a common neuropathological factor. Interestingly, we found that schizophrenic patients showed negative correlations between volumes of GM and WM in the ACC. Our whole-brain voxel-wise multimodal analysis did not yield any other cluster of significant correlation in either patients or controls. This finding is in line with the finding of another study which also demonstrated a negative correlation between the whole volume of GM and WM in schizophrenic patients [54]. Following those results and the idea of Benes et al. [55] that DNA fragmentation is decreased in the ACC in schizophrenia, it is tentative to speculate that neuronal degeneration leads to increased WM fiber density with a relative increase in laminar structures in the ACC. The observation of a dysfunctional morphology in the ACC of schizophrenic patients is also supported by further findings of our study. When we quantified the volumes of the ACS and PCS, we only found statistically significant differences in the ACS and IFS, with the schizophrenic patients showing significantly reduced volumes in comparison with the healthy controls. Taken together, our structural findings add to the increasing evidence of DMN abnormality in schizophrenia and seem to stress the central role of the ACC over other functionally and structurally related areas, such as the PCC, in the neuropathology of schizophrenia. The present study, as the majority of neuroimaging studies on severe mental disorders, was carried out on
patients who received pharmacological treatment. The influence of medication on structural volumes is controversial. A recent meta-analysis provided evidence that GM volumes in the ACC and related regions can be influenced by the exposure to antipsychotics; patients receiving medication were more likely to show structural abnormalities in these areas [31]. However, a previous meta-analysis came to the contrary conclusion that antipsychotic medication did not influence reductions in GM or WM [27]. In summary, we reported on evidence of medial-brain structural abnormalities in schizophrenia, stressing the role of the medial prefrontal cortex as a key region for the disorder. The negative correlation between GM and WM and decreased volumes of the sulci, limited to the medial frontal cortex, is a more particular and novel finding. Since structural alterations to GM and WM appear to occur at different times in schizophrenia and seem to be influenced by the duration and severity of the disorder, longitudinal studies examining GM and WM should be initiated to further understand the nature of the structural and also functional abnormalities in schizophrenia.
Cingulate Abnormalities in Schizophrenia
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
Acknowledgements This study was supported by grants from the French National Center for Scientific Research (CNRS). The authors thank the group of Centre IRMf de Marseille (J.L. Anton, B. Nazarian and M. Roth) for their technical support in imaging acquisition. Finally, we would like to thank Chris Racey for proofreading the manuscript and for his valuable advice. P. Salgado-Pineda and B.L. Amann are supported by the Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM). B.L. Amann receives grant support from the Instituto de Salud Carlos III with a Miguel Servet Research Contract (CP06/0359).
Disclosure Statement All authors declare that they have no conflicts of interest. There were no financial interests due to the pharmaceutical industry. The CNRS had not further role in the study design, in the writing of the report and in the decision to submit the paper for publication.
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Salgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
Structural Abnormalities in Schizophrenia: Further Evidence on the Key Role of the Anterior Cingulate Cortex P. Salgado-Pineda a, b R. Landin-Romero a E. Fakra c, d P. Delaveau e B.L. Amann a, b O. Blin c
a
FIDMAG Hermanas Hospitalarias Research Foundation, Sant Boi de Llobregat and b CIBERSAM, Barcelona, Spain; CIC-UPCET, Hôpital de la Timone, INCM, UMR CNRS 6193 and d Pôle Universitaire de Psychiatrie, CHU Sainte-Marguerite, APHM, Marseille, and e Centre Emotion, CNRS USR 3246, Groupe Hospitalier Pitié Salpêtrière, Paris, France c
Key Words Schizophrenia · Cingulate gyrus · Structural magnetic resonance imaging
Abstract Objective: The present study examined whole-brain structural abnormalities in schizophrenia, with a special focus on the anterior and posterior cingulate cortex (ACC, PCC) as this is an understudied issue in schizophrenia. Method: Wholebrain voxel-based morphometry analyses of gray matter (GM) and white matter (WM) were performed to detect volumetric differences between 14 patients with schizophrenia and 14 healthy controls matched for age, sex, educational level and parents’ educational level. We examined withingroup GM and WM correlations and completed the analysis with measurements of sulci in medial cortical areas. Results: Compared with the healthy controls, the schizophrenic patients showed significant decreases in GM volumes in the ACC and PCC, and in neighboring WM regions such as the corpus callosum and the fimbriae of the fornix. Moreover, the patient group also displayed a negative correlation between volumes of GM and WM in the ACC. Finally, the patients showed significantly reduced volumes in the right cingulate sulci and left inferior frontal sulci. Conclusion: Our re-
© 2014 S. Karger AG, Basel 0302–282X/14/0691–0052$39.50/0 E-Mail [email protected] www.karger.com/nps
sults replicate typical brain-structural abnormalities with new findings in the medial prefrontal cortex, suggested to be a key region in this disorder. © 2014 S. Karger AG, Basel
Introduction
During the past 30 years, remarkable progress has been made in the identification of structural brain changes in schizophrenia. Hereby, schizophrenia is characterized by a reduction in whole volume of around 2%, coupled with larger reductions in regions such as the frontal lobe and the hippocampus [1, 2]. Ellison-Wright and Bullmore [3] meta-analyzed 42 voxel-based morphometry (VBM) studies on schizophrenia and found gray matter (GM) volume reductions in the frontal, temporal, cingulate and insular cortices and the thalamus. Some VBM studies in schizophrenia have described GM abnormalities as also affecting the adjacent white matter (WM) regions [4]. Cerebral abnormalities in the cingulate gyrus play a crucial role in the cognitive dysfunction and emotional disturbances that characterize schizophrenia. In brief, the cingulate gyrus is a cortical area of mixed cytoarchitecDr. Pilar Salgado-Pineda FIDMAG Hermanas Hospitalarias Research Foundation, FIBERSAM c/o Dr. Antoni Pujadas, 38 ES–08830 Sant Boi de Llobregat, Barcelona (Spain) E-Mail psalgado @ hospitalbenitomenni.org
tonics that links the limbic system and the neocortex. It is subdivided into two components, which are separated on the basis of cytoarchitecture, projection patterns and functions [5]: (1) the anterior cingulate cortex (ACC), which plays an important role in emotional, cognitive/attentional and nociceptive functioning as well as motor processing, and (2) the posterior cingulate cortex (PCC), which has a prominent role in pain and memory retrieval and, along with the precuneus, is implicated in human awareness [6]. In an extensive review of that topic, the authors suggest in brief that schizophrenia deficits involve the cingulate cortex and especially the ACC, with negative consequences on executive functioning, selective attention, error detection, word generation, working memory and the evaluation of the emotional significance of events [7]. They also highlight that the majority of neuroimaging studies in schizophrenia reported a reduction in ACC and PCC GM volumes and WM alterations in these regions, using diffusion tensor imaging (DTI) analysis. Some studies on schizophrenia have demonstrated reductions in the volumes of both the ACC [8–13] and the PCC [14, 15], but other groups found no significant differences between schizophrenic patients and controls [16, 17], or even a larger left ACC volume – correlated with neuroleptic exposure – in schizophrenic patients than in healthy controls [18]. A recent study also found diminished cortical thickness in the PCC in schizophrenic patients, which was correlated with altered WM connectivity [19]. In a multimodal study, using VBM functional magnetic resonance imaging (MRI) and DTI combined with tractography, Pomarol-Clotet et al. [20] have reported convergent structural and functional abnormalities in a specific medial frontal region corresponding to the anterior midline node of the so-called ‘default mode network’ (DMN). The DMN has been implicated in self-directed mental activity, specifically including episodic memory retrieval, inner speech, mental imagery, emotions and planning of future events [21–24]. There is increasing evidence of DMN abnormalities in schizophrenia, and most studies report that both structural and functional changes are maximal in the medial frontal area which overlaps the anterior midline node of this network [25]. Using an emotional face recognition task in a group of 14 patients with schizophrenia, we have recently also demonstrated that, compared with healthy controls, schizophrenic patients showed deactivation failures in both the anterior and the posterior midline nodes of the DMN that were strongly correlated with GM volume reductions in the same areas [26].
Table 1. Clinical and demographic data on schizophrenic patients
Cingulate Abnormalities in Schizophrenia
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
and healthy controls
Age, years Age range, years Gender – male/female, n Education level, years Parents’ educational level, years Duration of illness, years Total PANSS score Negative factor Positive factor Excitation factor Cognitive factor Depression factor
Control group (n = 14)
Patient group (n = 14)
34.64±5.96 23–48 9/5 14.23±2.05 12.21±3.31 – – – – – – –
37.29±8.87 22–56 9/5 12.2±4.22 13.08±4.42 14±6.70 60.7±12.0 13.14±5.46 24.71±8.42 8.43±2.47 7.93±3.32 6.5±2.74
Values denote means ± SD unless otherwise indicated. PANSS = Positive and Negative Syndrome Scale.
The purpose of the present study was to explore structural brain differences, using a whole-brain approach but focusing on the ACC, PCC and neighboring WM regions in order to provide complementary information on the structural abnormalities typically found in schizophrenia. Based on the previous literature, we hypothesized significantly smaller GM volumes in the posterior and anterior nodes of the DMN and neighboring WM regions. Furthermore, we predicted a replication of changes in global gyrification in our patient sample, as suggested by previous studies on schizophrenic patients [27]. More specifically, differences in local gyrification were hypothesized a priori in the anterior cingulate sulcus (ACS) and the posterior cingulate sulcus (PCS), bilaterally.
Methods Participants The patient sample consisted of 14 right-handed schizophrenic patients recruited from the Department of Psychiatry of Sainte Marguerite Hospital in Marseille, France. They all met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria for schizophrenia, based on interviews and a review of the clinical history conducted by 2 psychiatrists. They all were scanned in a relatively stable clinical condition, based on scores on the Positive and Negative Syndrome Scale (table 1). All patients received neuroleptic medication, with 11 patients being treated with atypical antipsychotics (amisulpride, n = 3; risperidone, n = 3; olanzapine, n = 3; aripiprazole, n = 2) and 3 with atypical neuroleptics, in this case haloperidol.
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The controls consisted of 14 healthy subjects and they were matched for handedness, age, educational level and parental educational level. They had no history of psychiatric or neurological disease and no history of or current drug abuse or dependency. All participants in the current study were the same subjects from a previous multimodal study on schizophrenia [26]. The study was approved by the local ethics committee (Comité Consultatifs de Protection des Personnes se prêtant à des Recherches Biomédicales, Marseille). Each participant was registered in the French National File of Registrations and gave his/her written informed consent before entering the study. Neuroimaging Data Acquisition Three-dimensional anatomical images were acquired in a single MRI scanning session using a 3-Tesla scanner (Bruker, Ettlingen, Germany) at the functional MRI Center of Marseille, France. A set of high-resolution T1-weighted images was acquired using the following acquisition parameters: sagittal magnetization prepared rapid acquisition gradient echo sequence; TE/TR = 5/25 ms; TI = 800 ms; flip angle = 15°; and matrix = 256 × 256 × 128. Neuroimaging Data Analysis VBM Analysis The T1-weighted images were analyzed by the VBM technique using SPM5 software (Statistical Parametric Mapping; Wellcome Department of Cognitive Neurology, University College London, UK) implemented in Matlab 7.7.0 (Mathworks, Sherborn, Mass., USA). Briefly, VBM analysis is a comparison of tissue volumes between two groups of subjects [28]. The data have to be preprocessed by segmenting different tissue types and normalizing to the same anatomical space. Finally, a statistical parametric map shows regions where a concentration of a certain tissue type differs between groups. The data set was preprocessed using the unified segmentation approach [29] by estimating the model parameters for a maximum a posteriori solution alternating among classification, bias correction and registration steps in the same generative model. The registered images were then modulated to correct for regional expansion/shrinkage during spatial normalization. The data were spatially smoothed with an isotropic gaussian kernel of 12 mm of full-width half maximum. Statistical inference was made by wholebrain voxel-wise fitting of a general linear model, and statistical significance was corrected for multiple comparisons using the gaussian random field theory (RFT). Sulcus Measurement We used the Anatomist/BrainVISA 4.0 package (Neurosciences Cognitives et Imagerie Cérébrale, UPR 640-CNRS LENA) to identify and quantify the sulci. This software allows an automatic recognition of the main sulci of the human cortex. The representation nodes are cortical folds, which are given a sulcus name by a contextual pattern recognition method. The brain images were reoriented, segmented and processed following standard automatic methods contained in the BrainVISA software [30]. The first author (P.S.-P.) reviewed the results of the automated labeling and manually relabeled any incorrect sulci using the Atlas of the Cerebral Sulci [31]. For the purposes of the present study, we quantified the bilateral volumes (in cubic millimeters) of the ACS and PCS, the inferior frontal sulcus (IFS) and callosal sulcus (CS), bilaterally. Statistical analyses were per-
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Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
formed using the Statistical Package for the Social Sciences (SPSS Windows, version 12.0; SPSS Inc., Chicago, Ill., USA). Due to the small sample size, the data did not meet the assumption of a normal distribution (Shapiro-Wilk test; W statistic, p < 0.05). Therefore, we performed nonparametric analyses of variance between groups. Correlations between Volumes of GM and WM In order to assess the correlations between volumes of GM and WM in patients and controls, we performed a voxel-wise multimodal correlation using the biological parametric mapping (BPM) statistical toolbox [32]. The BPM toolbox incorporates information obtained from other modalities as regressors in a whole-brain voxel-wise analysis. The BPM toolbox uses the general linear model for statistical estimation, and RFT or false discovery rate (FDR) for statistical inference. We have used the implemented RFT-based inference for image correlation analysis, which is more appropriate in this context [32]. A threshold of p < 0.05 was used for all analyses.
Results
Demographic and Clinical Data The demographic and clinical data on the patient and control groups are shown in table 1. The groups were matched for handedness, age, educational level and parental educational level. There were no significant differences at p < 0.05 between the patients and controls in all demographic variables. Neuroimaging Results VBM Findings At an FDR-corrected p < 0.05, whole-brain differences in GM volume were localized medially, extending bilaterally from the anterior to the posterior cingulate gyrus (fig. 1). The patients showed reduced volumes compared with controls in the anterior (peak in Brodmann area, BA, 32; MNI coordinates: –12, 34, 17; z value = 4.49), central (peak in BA 24; MNI coordinates: –12, –15, 42; z value = 4.64) and posterior cingulate (peak in BA 30; MNI coordinates: 6, –46, 21; z value = 2.41), as well as in the medial frontal cortex (peaks in BA 9, MNI coordinates: –8, 42, 27, z value = 4.31, and in BA 11, z value = 4.22). These findings were basically a replication of those of from our previous study of GM reductions in patients with schizophrenia [26]. At an FDR-corrected p < 0.05, we found significant decreases in WM volume in the schizophrenia group compared with the controls in the corpus callosum and in the fimbriae of the fornix bilaterally (fig. 1). No increases in WM or GM were observed in our schizophrenia sample when compared with the controls. Salgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
Color version available online
Fig. 1. Decreases in GM (winter range) and WM (hot range; color online only) volumes in patients with schizo-
phrenia (n = 14) compared with healthy controls (n = 14).
Sulcus Measurements The descriptive values of the ACS, PCS, IFS and CS in each hemisphere for the two groups are summarized in table 2. The nonparametric analysis of variance revealed that, compared with the healthy subjects, the schizophrenic patients showed significantly reduced volumes in the right ACS (z = 3.033; p = 0.002) and left IFS (z = 2.205; p = 0.027). Correlations between Volumes of GM and WM A whole-brain analysis in the schizophrenia group yielded one cluster of significant negative correlation between the volumes of GM and WM in the ACC (BA 32; MNI coordinates: 2, 40, 19; Pearson’s correlation index = –0.82; p < 0.001). Although we did not find any cluster of significant correlation in the healthy controls, we decided to explore the relationship between GM and WM volumes and ACC cluster in healthy controls as well. Contrary to the patient group, we observed a positive tendency for a correlation Cingulate Abnormalities in Schizophrenia
between GM and WM only, without reaching statistical significance (Pearson’s correlation index = 0.45; p = 0.103; fig. 2).
Discussion
In the present study we replicated findings in schizophrenic patients, in comparison with healthy controls, of a structural abnormality in GM and WM that extended along the midline of the brain from the frontal to the occipital lobe. This pattern of structural abnormality involved several regions that have previously been reported on in the literature on structural abnormalities in schizophrenia, such as sections of the ACC and PCC and neighboring regions of the WM. However, some of our results, the negative correlation between GM and WM and decreased volumes of the sulci, were only limited to the ACC and are novel in the literature. Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
55
0.14
0.10
0.12
0.08
0.10 WM
WM
0.12
0.06 0.04
0.06
0.02
0.04
0
a
0.02 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 GM
Fig. 2. Scatter plot displaying within-group relationships between GM and WM in schizophrenic patients (a) and controls (b) in the
anterior cingulate gyrus (BA 32; MNI coordinates: 2, 40, 19). The patient group exhibited a significant negative correlation (Pear-
Table 2. Sulcus volumetric measurements in patient and control
groups
Right ACS Left ACS Right IFS Left IFS Right CS Left CS Right PCS Left PCS
Control group (n = 14) volume, mm3
Patient group (n = 14) volume, mm3
Between-group z
p1
780.15±568 742.65±178 1,118.50±152 1,064.73±465 491.03±381 504.16±291 875.95±273 728.58±230
326.40±229 649.33±282 961.15±340 737.48±357 380.09±269 391.93±274 678.96±316 597.48±171
3.033 0.965 0.191 2.205 0.322 1.103 1.608 1.608
0.002* 0.352 0.376 0.027* 0.769 0.285 0.114 0.114
Values denote means ± SD unless specified otherwise. * Significant statistical difference. 1 All p values FDR corrected.
Compared with the healthy controls, the schizophrenic patients showed decreased GM volumes localized medially and extending bilaterally from the anterior to the posterior cingulate gyrus. These volumetric cingulate abnormalities in schizophrenic patients are in agreement with the theory of aberrant maturation of the brain. A recent study by Supekar et al. [33] reported convergent structural and functional connectivity results, suggesting that the posterior cingulate-medial prefrontal connectivity along the cingulum bundle is the most immature link in the DMN of children compared with young adults. The authors proposed that the maturation of the PCC-medial 56
0.08
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
b
0.4
0.5
0.6
0.7
GM
0.8
0.9
1.0
1.1
son’s correlation index = –0.82; p < 0.001) between the volumes of WM and GM. The healthy controls presented a WM and GM relationship with a positive tendency that did not reach statistical significance (Pearson’s correlation index = 0.45; p = 0.103).
prefrontal cortex connectivity plays an important role in the development of self-related and sociocognitive functions that emerge during adolescence. An abnormal maturation of these brain networks could explain the social and cognitive impairment in schizophrenia, and a dysfunction of these regions could be essential in children at risk for the disorder. The schizophrenic patients of our study showed reduced WM volumes in the entire corpus callosum. Postmortem studies of the corpus callosum in schizophrenia have reported anatomical dysmorphology expressed as increased/decreased thickness, decreased cross-sectional area or decreased fiber density [34–36]. MRI studies have reported callosal abnormalities in schizophrenia, although results across studies have not always been in agreement (for a review, see [37]). In a recent meta-analysis, Arnone et al. [38] analyzed the data from 28 MRI studies assessing callosal volumes in schizophrenic patients compared with healthy subjects and confirmed the presence of reduced callosal areas in schizophrenia. DTI analyses have also reported abnormalities in the integrity of the corpus callosum in schizophrenia [39–42]. The patients of our study also showed reduced WM volumes in the fimbriae of the fornix bilaterally. The fimbria of the fornix is the main hippocampal output, one of the most frequently implicated brain structures, which has been consistently reported to be abnormal in schizophrenia [1, 37, 43–48]. Few studies have investigated the fornix in schizophrenia, reporting contradictory results. Zahajszky et al. [49] found no MRI volumetric differences between healthy controls and patients with chronic schizoSalgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
phrenia. In contrast, Davies et al. [50] showed an increase in volume in the cross-sectional area of the fornix in earlyonset schizophrenia. In the only post-mortem study evaluating the fornix, increased fiber densities in the left fornix of male subjects with schizophrenia were found [51]. Two recent DTI studies assessed WM integrity in the fornix in schizophrenia. One reported a decrease in fiber integrity in subjects with chronic schizophrenia compared with healthy controls [52], while the other found a bilateral disruption in fornix integrity in schizophrenia [53]. Together, our findings of reduced GM and WM volumes support the classic notion of a frontostriatal structural abnormality in schizophrenia. In this context, a recent multimodal voxel-wise meta-analysis of 79 studies revealed overlapping GM and WM structural findings in schizophrenia [4]. Among the regions, they especially highlighted alterations in limbic and subcortical structures, GM abnormalities in the bilateral prefrontal cortex and WM changes, including tracts that connect these structures within them and between hemispheres. The authors argue that these overlapping GM and WM abnormalities might be secondary to each other or represent a marker of a common neuropathological factor. Interestingly, we found that schizophrenic patients showed negative correlations between volumes of GM and WM in the ACC. Our whole-brain voxel-wise multimodal analysis did not yield any other cluster of significant correlation in either patients or controls. This finding is in line with the finding of another study which also demonstrated a negative correlation between the whole volume of GM and WM in schizophrenic patients [54]. Following those results and the idea of Benes et al. [55] that DNA fragmentation is decreased in the ACC in schizophrenia, it is tentative to speculate that neuronal degeneration leads to increased WM fiber density with a relative increase in laminar structures in the ACC. The observation of a dysfunctional morphology in the ACC of schizophrenic patients is also supported by further findings of our study. When we quantified the volumes of the ACS and PCS, we only found statistically significant differences in the ACS and IFS, with the schizophrenic patients showing significantly reduced volumes in comparison with the healthy controls. Taken together, our structural findings add to the increasing evidence of DMN abnormality in schizophrenia and seem to stress the central role of the ACC over other functionally and structurally related areas, such as the PCC, in the neuropathology of schizophrenia. The present study, as the majority of neuroimaging studies on severe mental disorders, was carried out on
patients who received pharmacological treatment. The influence of medication on structural volumes is controversial. A recent meta-analysis provided evidence that GM volumes in the ACC and related regions can be influenced by the exposure to antipsychotics; patients receiving medication were more likely to show structural abnormalities in these areas [31]. However, a previous meta-analysis came to the contrary conclusion that antipsychotic medication did not influence reductions in GM or WM [27]. In summary, we reported on evidence of medial-brain structural abnormalities in schizophrenia, stressing the role of the medial prefrontal cortex as a key region for the disorder. The negative correlation between GM and WM and decreased volumes of the sulci, limited to the medial frontal cortex, is a more particular and novel finding. Since structural alterations to GM and WM appear to occur at different times in schizophrenia and seem to be influenced by the duration and severity of the disorder, longitudinal studies examining GM and WM should be initiated to further understand the nature of the structural and also functional abnormalities in schizophrenia.
Cingulate Abnormalities in Schizophrenia
Neuropsychobiology 2014;69:52–58 DOI: 10.1159/000356972
Acknowledgements This study was supported by grants from the French National Center for Scientific Research (CNRS). The authors thank the group of Centre IRMf de Marseille (J.L. Anton, B. Nazarian and M. Roth) for their technical support in imaging acquisition. Finally, we would like to thank Chris Racey for proofreading the manuscript and for his valuable advice. P. Salgado-Pineda and B.L. Amann are supported by the Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM). B.L. Amann receives grant support from the Instituto de Salud Carlos III with a Miguel Servet Research Contract (CP06/0359).
Disclosure Statement All authors declare that they have no conflicts of interest. There were no financial interests due to the pharmaceutical industry. The CNRS had not further role in the study design, in the writing of the report and in the decision to submit the paper for publication.
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Salgado-Pineda/Landin-Romero/Fakra/ Delaveau/Amann/Blin
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