Hostname: page-component-594f858ff7-hf9kg Total loading time: 0 Render date: 2023-06-06T19:01:46.835Z Has data issue: false Feature Flags: { "corePageComponentGetUserInfoFromSharedSession": false, "coreDisableEcommerce": false, "corePageComponentUseShareaholicInsteadOfAddThis": true, "coreDisableSocialShare": false, "useRatesEcommerce": true } hasContentIssue false

Multimodal meta-analysis of structural gray matter, neurocognitive and social cognitive fMRI findings in schizophrenia patients

Published online by Cambridge University Press:  07 February 2022

Maria Picó-Pérez
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal Clinical Academic Center – Braga, Braga, Portugal
Rita Vieira
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal Clinical Academic Center – Braga, Braga, Portugal
Marcos Fernández-Rodríguez
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
Maria Antónia Pereira De Barros
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal
Joaquim Radua
Imaging of Mood- and Anxiety-Related Disorders (IMARD) Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet, Stockholm, Sweden Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK Mental Health Research Networking Center (CIBERSAM), Barcelona, Spain
Pedro Morgado*
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal Clinical Academic Center – Braga, Braga, Portugal
Author for correspondence: Pedro Morgado, E-mail:


Neuroimaging research has shown that patients with schizophrenia (SCZ) present brain structural and functional alterations, but the results across imaging modalities and task paradigms are difficult to reconcile. Specifically, no meta-analyses have tested whether the same brain systems that are structurally different in SCZ patients are also involved in neurocognitive and social cognitive tasks. To answer this, we conducted separate meta-analyses of voxel-based morphometry, neurocognitive functional magnetic resonance imaging (fMRI), and social cognitive fMRI studies. Next, with a multimodal approach, we identified the common alterations across meta-analyses. Further exploratory meta-analyses were performed taking into account several clinical variables (illness duration, medication status, and symptom severity). A cluster covering the dorsomedial prefrontal cortex (dmPFC) and the supplementary motor area (SMA), and the right inferior frontal gyrus (IFG), presented shared structural and neurocognitive-related activation decreases, while the right angular gyrus presented shared decreases between structural and social cognitive-related activation. The exploratory meta-analyses replicated to some extent these findings, while new regions of alterations appeared in patient subgroups with specific clinical features. In conclusion, we found task-specific correlates of brain structure and function in SCZ, which help summarize and integrate a growing literature.

Review Article
Copyright © The Author(s), 2022. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)


Albajes-Eizagirre, A., Solanes, A., Fullana, M. A., Ioannidis, J. P. A., Fusar-Poli, P., Torrent, C., … Radua, J. (2019a). Meta-analysis of voxel-based neuroimaging studies using seed-based d mapping with permutation of subject images (SDM-PSI). Journal of Visualized Experiments, 153(e59841), 17. Scholar
Albajes-Eizagirre, A., Solanes, A., & Radua, J. (2019b). Meta-analysis of non-statistically significant unreported effects. Statistical Methods in Medical Research, 28(12), 37413754. ScholarPubMed
Albajes-Eizagirre, A., Solanes, A., Vieta, E., & Radua, J. (2019c). Voxel-based meta-analysis via permutation of subject images (PSI): Theory and implementation for SDM. NeuroImage, 186, 174184. ScholarPubMed
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association.Google Scholar
Anticevic, A., Van Snellenberg, J. X., Cohen, R. E., Repovs, G., Dowd, E. C., & Barch, D. M. (2012). Amygdala recruitment in schizophrenia in response to aversive emotional material: A meta-analysis of neuroimaging studies. Schizophrenia Bulletin, 38(3), 608621. ScholarPubMed
Baiano, M., David, A., Versace, A., Churchill, R., Balestrieri, M., & Brambilla, P. (2007). Anterior cingulate volumes in schizophrenia: A systematic review and a meta-analysis of MRI studies. Schizophrenia Research, 93(1–3), 112. Scholar
Barch, D. M., Csernansky, J. G., Conturo, T., & Snyder, A. Z. (2002). Working and long-term memory deficits in schizophrenia: Is there a common prefrontal mechanism? Journal of Abnormal Psychology, 111(3), 478494. Scholar
Barta, P. E., Pearlson, G. D., Powers, R. E., Richards, S. S., & Tune, L. E. (1990). Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia. American Journal of Psychiatry, 147(11), 14571462. ScholarPubMed
Calhoun, V. D., & Sui, J. (2016). Multimodal fusion of brain imaging data: A key to finding the missing link(s) in complex mental illness. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 1(3), 230. Scholar
Cannon, T. D., van Erp, T. G. M., Bearden, C. E., Loewy, R., Thompson, P., Toga, A. W., … Tsuang, M. T. (2003). Early and late neurodevelopmental influences in the prodrome to schizophrenia: Contributions of genes, environment, and their interactions. Schizophrenia Bulletin, 29(4), 653669. ScholarPubMed
Chan, R. C. K., Di, X., McAlonan, G. M., & Gong, Q. Y. (2011). Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: An activation likelihood estimation meta-analysis of illness progression. Schizophrenia Bulletin, 37(1), 177188. ScholarPubMed
Ding, Y., Ou, Y., Pan, P., Shan, X., Chen, J., Liu, F., … Guo, W. (2019). Cerebellar structural and functional abnormalities in first-episode and drug-naive patients with schizophrenia: A meta-analysis. Psychiatry Research - Neuroimaging, 283, 2433. ScholarPubMed
Fett, A. K. J., Viechtbauer, W., Dominguez, M. de G., Penn, D. L., van Os, J., & Krabbendam, L. (2011). The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: A meta-analysis. Neuroscience and Biobehavioral Reviews, 35(3), 573588. ScholarPubMed
Fornara, G. A., Papagno, C., & Berlingeri, M. (2017). A neuroanatomical account of mental time travelling in schizophrenia: A meta-analysis of functional and structural neuroimaging data. Neuroscience and Biobehavioral Reviews, 80, 211222. ScholarPubMed
Fornito, A., Yücel, M., Dean, B., Wood, S. J., & Pantelis, C. (2009). Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: Bridging the gap between neuroimaging and neuropathology. Schizophrenia Bulletin, 35(5), 973993. ScholarPubMed
Fusar-Poli, P., Broome, M. R., Woolley, J. B., Johns, L. C., Tabraham, P., Bramon, E., … McGuire, P. (2011). Altered brain function directly related to structural abnormalities in people at ultra-high risk of psychosis: Longitudinal VBM-fMRI study. Journal of Psychiatric Research, 45(2), 190198. ScholarPubMed
Fusar-Poli, P., Deste, G., Smieskova, R., Barlati, S., Yung, A. R., Howes, O., … Borgwardt, S. (2012). Cognitive functioning in prodromal psychosis: A meta-analysis. Archives of General Psychiatry, 69(6), 562571. ScholarPubMed
Galderisi, S., DeLisi, L. E., & Borgwardt, S. (2019). Neuroimaging of schizophrenia and other primary psychotic disorders: Achievements and perspectives. In Galderisi, Silvana, DeLisi, Lynn E., & Borgwardt, Stefan (Eds.), Neuroimaging of schizophrenia and other primary psychotic disorders: Achievements and perspectives (pp. 1345). New York: Springer International Publishing. Scholar
Gao, X., Zhang, W., Yao, L., Xiao, Y., Liu, L., Liu, J., … Lui, S. (2018). Association between structural and functional brain alterations in drug-free patients with schizophrenia: A multimodal meta-analysis. Journal of Psychiatry and Neuroscience, 43(2), 131142. ScholarPubMed
Glantz, L. A., & Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Archives of General Psychiatry, 57(1), 6573. ScholarPubMed
Green, M. F., Nuechterlein, K. H., Gold, J. M., Barch, D. M., Cohen, J., Essock, S., … Marder, S. R. (2004). Approaching a consensus cognitive battery for clinical trials in schizophrenia: The NIMH-MATRICS conference to select cognitive domains and test criteria. Biological Psychiatry, 56(5), 301307. ScholarPubMed
Green, M. F., Penn, D. L., Bentall, R., Carpenter, W. T., Gaebel, W., Gur, R. C., … Heinssen, R. (2008). Social cognition in schizophrenia: An NIMH workshop on definitions, assessment, and research opportunities. Schizophrenia Bulletin, 34(6), 12111220. ScholarPubMed
Guimond, S., Padani, S., Lutz, O., Eack, S., Thermenos, H., & Keshavan, M. (2018). Impaired regulation of emotional distractors during working memory load in schizophrenia. Journal of Psychiatric Research, 101(May 2017), 1420. ScholarPubMed
Hu, M. L., Zong, X. F., Mann, J. J., Zheng, J. J., Liao, Y. H., Li, Z. C., … Tang, J. S. (2017). A review of the functional and anatomical default mode network in schizophrenia. Neuroscience Bulletin, 33(1), 7384. ScholarPubMed
Huang, H., Botao, Z., Jiang, Y., Tang, Y., Zhang, T., Tang, X., … Wang, J. (2019). Aberrant resting-state functional connectivity of salience network in first-episode schizophrenia. Brain Imaging and Behavior, 14, 111. Scholar
Ioakeimidis, V., Haenschel, C., Yarrow, K., Kyriakopoulos, M., & Dima, D. (2020). A meta-analysis of structural and functional brain abnormalities in early-onset schizophrenia. Schizophrenia Bulletin Open, 1(1), 112. Scholar
Jáni, M., & Kašpárek, T. (2018). Emotion recognition and theory of mind in schizophrenia: A meta-analysis of neuroimaging studies. World Journal of Biological Psychiatry, 19(S3), S86S96. ScholarPubMed
Jiménez, J. A., Mancini-Marïe, A., Lakis, N., Rinaldi, M., & Mendrek, A. (2010). Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia. Schizophrenia Research, 122(1–3), 5362. ScholarPubMed
Karlsgodt, K. H., Sun, D., & Cannon, T. D. (2010). Structural and functional brain abnormalities in schizophrenia. Current Directions in Psychological Science, 19(4), 226. ScholarPubMed
Kay, S. R., Fiszbein, A., Lindenmayer, J.-P., & Opler, L. A. (1986). Positive and negative syndromes in schizophrenia as a function of chronicity. Acta Psychiatrica Scandinavica, 74(5), 507518. ScholarPubMed
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13(2), 261276. ScholarPubMed
Kuo, S. S., & Pogue-Geile, M. F. (2019). Variation in fourteen brain structure volumes in schizophrenia: A comprehensive meta-analysis of 246 studies. Neuroscience and Biobehavioral Reviews, 98, 8594. ScholarPubMed
Lee, H., Lee, D. K., Park, K., Kim, C. E., & Ryu, S. (2019). Default mode network connectivity is associated with long-term clinical outcome in patients with schizophrenia. NeuroImage: Clinical, 22, 101805. ScholarPubMed
Li, H., Chan, R. C. K., McAlonan, G. M., & Gong, Q. Y. (2010). Facial emotion processing in schizophrenia: A meta-analysis of functional neuroimaging data. Schizophrenia Bulletin, 36(5), 10291039. ScholarPubMed
Li, W., Mai, X., & Liu, C. (2014). The default mode network and social understanding of others: What do brain connectivity studies tell us. Frontiers in Human Neuroscience, 8(74), 115. ScholarPubMed
Liddle, P. F. (2000). Cognitive impairment in schizophrenia: Its impact on social functioning. Acta Psychiatrica Scandinavica, Supplement, 101(400), 1116.[dash]3.x.CrossRefGoogle Scholar
Lui, S., Yao, L., Xiao, Y., Keedy, S. K., Reilly, J. L., Keefe, R. S., … Sweeney, J. A. (2015). Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives. Psychological Medicine, 45(1), 97108. ScholarPubMed
Luo, Q., Chen, Q., Wang, W., Desrivières, S., Quinlan, E. B., & Jia, T., … consortium, for the I. (2019). Association of a schizophrenia-risk nonsynonymous variant with putamen volume in adolescents: A voxelwise and genome-wide association study. JAMA Psychiatry, 76(4), 435445. ScholarPubMed
Menon, V. (2015). Salience network. In Toga, A. W. (Ed.), Brain mapping: An encyclopedic reference (pp. 597611). New York: Academic Press: Elsevier.CrossRefGoogle Scholar
Menon, V., & Uddin, L. Q. (2010). Saliency, switching, attention and control: A network model of insula function. Brain Structure & Function, 214(5–6), 655667. ScholarPubMed
Minzenberg, M. J., Laird, A. R., Thelen, S., Carter, C. S., & Glahn, D. C. (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Archives of General Psychiatry, 66(8), 811822. ScholarPubMed
Müller, V. I., Cieslik, E. C., Laird, A. R., Fox, P. T., Radua, J., Mataix-Cols, D., … Eickhoff, S. B. (2018). Ten simple rules for neuroimaging meta-analysis. Neuroscience and Biobehavioral Reviews, 84, 151161. ScholarPubMed
Nuechterlein, K. H., Barch, D. M., Gold, J. M., Goldberg, T. E., Green, M. F., & Heaton, R. K. (2004). Identification of separable cognitive factors in schizophrenia. Schizophrenia Research, 72(1), 2939. ScholarPubMed
Pelletier-Baldelli, A., Bernard, J., & Mittal, V. (2015). Intrinsic functional connectivity in salience and default mode networks and aberrant social processes in youth at ultra-high risk for psychosis. PLoS One, 10(8), e0134936. ScholarPubMed
Pessoa, L., Kastner, S., & Ungerleider, L. G. (2003). Neuroimaging studies of attention: From modulation of sensory processing to top-down control. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(10), 39903998. Retrieved from ScholarPubMed
Picó-Pérez, M., Silva, P., De Melo, V., Radua, J., Mataix-Cols, D., Sousa, N., … Morgado, P. (2020). Modality-specific overlaps in brain structure and function in obsessive-compulsive disorder: Multimodal meta-analysis of case-control MRI studies. Neuroscience and Biobehavioral Reviews, 112, 8394. ScholarPubMed
Plis, S. M., Amin, M. F., Chekroud, A., Hjelm, D., Damaraju, E., Lee, H. J., … Calhoun, V. D. (2018). Reading the (functional) writing on the (structural) wall: Multimodal fusion of brain structural and function via a deep neural network based translation approach reveals novel impairments in schizophrenia. NeuroImage, 181, 734. Scholar
Radua, J., Borgwardt, S., Crescini, A., Mataix-Cols, D., Meyer-Lindenberg, A., McGuire, P. K., & Fusar-Poli, P. (2012). Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neuroscience and Biobehavioral Reviews, 36(10), 23252333. ScholarPubMed
Radua, J., Romeo, M., Mataix-Cols, D., & Fusar-Poli, P. (2013). A general approach for combining voxel-based meta-analyses conducted in different neuroimaging modalities. Current Medicinal Chemistry, 20(3), 462466. ScholarPubMed
Radua, J., Vieta, E., Shinohara, R., Kochunov, P., Quidé, Y., Green, M. J., … Pineda-Zapata, J. (2020). Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA. NeuroImage, 218, 116956. ScholarPubMed
Reed, R. A., Harrow, M., Herbener, E. S., & Martin, E. M. (2002). Executive function in schizophrenia: Is it linked to psychosis and poor life functioning? Journal of Nervous and Mental Disease, 190(11), 725732. ScholarPubMed
Satterthwaite, T. D., Wolf, D. H., Calkins, M. E., Vandekar, S. N., Erus, G., Ruparel, K., … Gur, R. E. (2016). Structural brain abnormalities in youth with psychosis spectrum symptoms. JAMA Psychiatry, 73(5), 515524. ScholarPubMed
Schultz, C. C., Fusar-Poli, P., Wagner, G., Koch, K., Schachtzabel, C., Gruber, O., … Schlösser, R. G. M. (2012). Multimodal functional and structural imaging investigations in psychosis research. European Archives of Psychiatry and Clinical Neuroscience 262(2), 97106. ScholarPubMed
Shenton, M. E., Kikinis, R., Jolesz, F. A., Pollak, S. D., LeMay, M., Wible, C. G., … McCarley, R. W. (1992). Abnormalities of the left temporal lobe and thought disorder in schizophrenia. New England Journal of Medicine, 327(9), 604612. ScholarPubMed
Taylor, S. F., Kang, J., Brege, I. S., Tso, I. F., Hosanagar, A., & Johnson, T. D. (2012). Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia. Biological Psychiatry, 71(2), 136145. ScholarPubMed
Vita, A., De Peri, L., Silenzi, C., & Dieci, M. (2006). Brain morphology in first-episode schizophrenia: A meta-analysis of quantitative magnetic resonance imaging studies. Schizophrenia Research, 82(1), 7588. ScholarPubMed
Wolf, D. H., Gur, R. C., Valdez, J. N., Loughead, J., Elliott, M. A., Gur, R. E., & Ragland, J. D. (2007). Alterations of fronto-temporal connectivity during word encoding in schizophrenia. Psychiatry Research – Neuroimaging, 154(3), 221232. ScholarPubMed
Zmigrod, L., Garrison, J. R., Carr, J., & Simons, J. S. (2016). The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies. Neuroscience and Biobehavioral Reviews, 69, 113123. ScholarPubMed
Supplementary material: File

Picó-Pérez et al. supplementary material

Picó-Pérez et al. supplementary material

Download Picó-Pérez et al. supplementary material(File)
File 752 KB