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Functional brain abnormalities of cognitive impairments in schizophrenia indicating higher integration of working memory than other domains

Molecular Psychiatry (2026)Cite this article

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Abstract

Brain functional alterations associated with overall cognitive impairments and specific cognitive domains defined by MATRICS Consensus Cognitive Battery (MCCB) and the similarities among them remain unclear in schizophrenia. Comprehensive literature review and meta-analyses of cognitive task fMRI studies were conducted to identify whole-brain differences between schizophrenia patients and healthy controls, and subgroup analyses were also conducted for each MCCB domain. Identified brain regions were mapped onto canonical brain networks. The similarity analyses between network dysfunction obtained for paired subgroup analyses with and without each MCCB domain, and between each MCCB domain and primary analysis, were calculated after controlling for sample size. Meta-regression analyses were conducted between brain alterations and demographic and clinical characteristics. The present meta-analysis encompassed 232 datasets with 5229 schizophrenia patients and 6132 healthy controls. In primary analysis, schizophrenia patients showed significant brain dysfunctions mainly within default mode and subcortical networks. Distinct brain dysfunctions for each MCCB domain were also identified. Sample size-weighted similarity analyses revealed that network alterations associated with working memory deficits, among the seven, showed the greatest convergence with brain changes identified in subgroup analysis without this domain and primary analysis (sample size-weighted Dice coefficients = 0.24 and 0.51). Significant correlations were identified between significant brain alterations and negative symptoms and years of education. Aberrant activations in default mode and subcortical networks in working memory domain showed higher similarity than those observed in the other six cognitive domains, indicating functional integration of working memory and functional specialization of remaining cognitive domains in schizophrenia.

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Fig. 1: Flowchart of the literature search and selection.
Fig. 2: The meta-analysis results in the primary analysis that combined all studies.
Fig. 3: Network alteration mapping analyses of higher, lower brain activation pattern and combined brain dysfunctions in primary analysis and each MCCB domain.
Fig. 4: The sample size-weighted Dice coefficient of brain dysfunctional activations among the cognitive domains.

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Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request.

References

  1. McCutcheon RA, Keefe RSE, McGuire PK. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry. 2023;28:1902–18.

    Article  PubMed  PubMed Central  Google Scholar 

  2. August SM, Kiwanuka JN, McMahon RP, Gold JM. The MATRICS Consensus Cognitive Battery (MCCB): clinical and cognitive correlates. Schizophr Res. 2012;134:76–82.

    Article  PubMed  Google Scholar 

  3. Howes OD, Bukala BR, Beck K. Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol. 2024;20:22–35.

    Article  PubMed  Google Scholar 

  4. Catalan A, Salazar de Pablo G, Aymerich C, Damiani S, Sordi V, Radua J, et al. Neurocognitive functioning in individuals at clinical high risk for psychosis: a systematic review and meta-analysis. JAMA Psychiatry. 2021;78:859–67.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Green MF, Horan WP, Lee J. Nonsocial and social cognition in schizophrenia: current evidence and future directions. World Psychiatry. 2019;18:146–61.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gold JM, Goldberg RW, McNary SW, Dixon LB, Lehman AF. Cognitive correlates of job tenure among patients with severe mental illness. Am J Psychiatry. 2002;159:1395–402.

    Article  PubMed  Google Scholar 

  7. Jauhar S, Johnstone M, McKenna PJ. Schizophrenia. Lancet. 2022;399:473–86.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang W, Sweeney JA, Bishop JR, Gong Q, Lui S. Biological subtyping of psychiatric syndromes as a pathway for advances in drug discovery and personalized medicine. Nat Ment Health. 2023;1:88–99.

    Article  Google Scholar 

  9. Su W, Wang J, Tang Y. A narrative literature review of white matter microstructure in individuals at clinical high risk for psychosis. Psychoradiology. 2025;5:kkae031.

    Article  PubMed  Google Scholar 

  10. Glahn DC, Ragland JD, Abramoff A, Barrett J, Laird AR, Bearden CE, et al. Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005;25:60–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Achim AM, Lepage M. Episodic memory-related activation in schizophrenia: meta-analysis. Br J Psychiatry. 2005;187:500–9.

    Article  PubMed  Google Scholar 

  12. Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC. Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry. 2009;66:811–22.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang W, Lei D, Keedy SK, Ivleva EI, Eum S, Yao L, et al. Brain gray matter network organization in psychotic disorders. Neuropsychopharmacology. 2020;45:666–74.

    Article  PubMed  Google Scholar 

  14. McTeague LM, Huemer J, Carreon DM, Jiang Y, Eickhoff SB, Etkin A. Identification of common neural circuit disruptions in cognitive control across psychiatric disorders. Am J Psychiatry. 2017;174:676–85.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Silver H, Feldman P, Bilker W, Gur RC. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am J Psychiatry. 2003;160:1809–16.

    Article  PubMed  Google Scholar 

  16. Bijsterbosch J, Harrison SJ, Jbabdi S, Woolrich M, Beckmann C, Smith S, et al. Challenges and future directions for representations of functional brain organization. Nat Neurosci. 2020;23:1484–95.

    Article  CAS  PubMed  Google Scholar 

  17. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. The MATRICS consensus cognitive battery, part 1: test selection, reliability, and validity. Am J Psychiatry. 2008;165:203–13.

    Article  PubMed  Google Scholar 

  18. Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, Gold JM, et al. The MATRICS consensus cognitive battery, part 2: co-norming and standardization. Am J Psychiatry. 2008;165:214–20.

    Article  PubMed  Google Scholar 

  19. Voineskos AN, Hawco C, Neufeld NH, Turner JA, Ameis SH, Anticevic A, et al. Functional magnetic resonance imaging in schizophrenia: current evidence, methodological advances, limitations and future directions. World Psychiatry. 2024;23:26–51.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Smallwood J, Bernhardt BC, Leech R, Bzdok D, Jefferies E, Margulies DS. The default mode network in cognition: a topographical perspective. Nat Rev Neurosci. 2021;22:503–13.

    Article  CAS  PubMed  Google Scholar 

  21. Farahani FV, Karwowski W, Lighthall NR. Application of graph theory for identifying connectivity patterns in human brain networks: a systematic review. Front Neurosci. 2019;13:585.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Picó-Pérez M, Vieira R, Fernández-Rodríguez M, De Barros MAP, Radua J, Morgado P. Multimodal meta-analysis of structural gray matter, neurocognitive and social cognitive fMRI findings in schizophrenia patients. Psychol Med. 2022;52:614–24.

    Article  PubMed  Google Scholar 

  23. Khalil M, Hollander P, Raucher-Chéné D, Lepage M, Lavigne KM. Structural brain correlates of cognitive function in schizophrenia: a meta-analysis. Neurosci Biobehav Rev. 2022;132:37–49.

    Article  PubMed  Google Scholar 

  24. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53:1119–29.

    Article  CAS  PubMed  Google Scholar 

  25. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). Cochrane. 2024. www.cochrane.org/handbook.

  26. Tahmasian M, Sepehry AA, Samea F, Khodadadifar T, Soltaninejad Z, Javaheripour N, et al. Practical recommendations to conduct a neuroimaging meta-analysis for neuropsychiatric disorders. Hum Brain Mapp. 2019;40:5142–54.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Radua J, Mataix-Cols D, Phillips ML, El-Hage W, Kronhaus DM, Cardoner N, et al. A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. Eur Psychiatry. 2012;27:605–11.

    Article  CAS  PubMed  Google Scholar 

  28. Radua J, van den Heuvel OA, Surguladze S, Mataix-Cols D. Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders. Arch Gen Psychiatry. 2010;67:701–11.

    Article  PubMed  Google Scholar 

  29. Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125–65.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zou KH, Warfield SK, Bharatha A, Tempany CM, Kaus MR, Haker SJ, et al. Statistical validation of image segmentation quality based on a spatial overlap index. Acad Radiol. 2004;11:178–89.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Alexander-Bloch AF, Shou H, Liu S, Satterthwaite TD, Glahn DC, Shinohara RT, et al. On testing for spatial correspondence between maps of human brain structure and function. Neuroimage. 2018;178:540–51.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhao Y, Zhang Q, Shah C, Li Q, Sweeney JA, Li F, et al. Cortical thickness abnormalities at different stages of the illness course in schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2022;79:560–70.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Johnson MK, McMahon RP, Robinson BM, Harvey AN, Hahn B, Leonard CJ, et al. The relationship between working memory capacity and broad measures of cognitive ability in healthy adults and people with schizophrenia. Neuropsychology. 2013;27:220–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yamashita M, Yoshihara Y, Hashimoto R, Yahata N, Ichikawa N, Sakai Y, et al. A prediction model of working memory across health and psychiatric disease using whole-brain functional connectivity. Elife. 2018;7:e38844.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gold JM, Luck SJ. Working memory in people with schizophrenia. Curr Top Behav Neurosci. 2023;63:137–52.

    Article  CAS  PubMed  Google Scholar 

  36. Gold JM, Barch DM, Feuerstahler LM, Carter CS, MacDonald AW, Ragland JD, et al. Working memory impairment across psychotic disorders. Schizophr Bull. 2019;45:804–12.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Damgaard V, Schandorff JM, Macoveanu J, Sankar A, Zarp J, Fisher PM, et al. Network-wide aberrancies in neuronal activity during working memory in a large cohort of patients with mood disorders: associations with cognitive impairment and functional disability. Mol Psychiatry. 2025;30:4836–44.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Anticevic A, Cole MW, Murray JD, Corlett PR, Wang XJ, Krystal JH. The role of default network deactivation in cognition and disease. Trends Cogn Sci. 2012;16:584–92.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Floresco SB, Braaksma DN, Phillips AG. Thalamic-cortical-striatal circuitry subserves working memory during delayed responding on a radial arm maze. J Neurosci. 1999;19:11061–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cao H, Argyelan M, Yan J, Velioglu HA, Fang F, Joanlanne A, et al. Mapping cerebellar connectivity to cognition in psychosis: convergent evidence from functional magnetic resonance imaging and transcranial magnetic stimulation. Biol Psychiatry. 2025;99:134–41.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Whitfield-Gabrieli S, Thermenos HW, Milanovic S, Tsuang MT, Faraone SV, McCarley RW, et al. Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia. Proc Natl Acad Sci USA. 2009;106:1279–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, Sweeney JA. Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2012;51:157–70.e5.

    Article  PubMed  Google Scholar 

  43. Van Snellenberg JX, Girgis RR, Horga G, van de Giessen E, Slifstein M, Ojeil N, et al. Mechanisms of working memory impairment in schizophrenia. Biol Psychiatry. 2016;80:617–26.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Barch DM, Sheffield JM. Cognitive impairments in psychotic disorders: common mechanisms and measurement. World Psychiatry. 2014;13:224–32.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bolkan SS, Stujenske JM, Parnaudeau S, Spellman TJ, Rauffenbart C, Abbas AI, et al. Thalamic projections sustain prefrontal activity during working memory maintenance. Nat Neurosci. 2017;20:987–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cao H, Chén OY, Chung Y, Forsyth JK, McEwen SC, Gee DG, et al. Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization. Nat Commun. 2018;9:3836.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cattaneo Z, Ferrari C, Ciricugno A, Heleven E, Schutter D, Manto M, et al. New horizons on non-invasive brain stimulation of the social and affective cerebellum. Cerebellum. 2022;21:482–96.

    Article  CAS  PubMed  Google Scholar 

  48. Cao H, Cannon TD. Cerebellar dysfunction and schizophrenia: from “Cognitive Dysmetria” to a potential therapeutic target. Am J Psychiatry. 2019;176:498–500.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Knowles EE, David AS, Reichenberg A. Processing speed deficits in schizophrenia: reexamining the evidence. Am J Psychiatry. 2010;167:828–35.

    Article  PubMed  Google Scholar 

  50. Sheffield JM, Barch DM. Cognition and resting-state functional connectivity in schizophrenia. Neurosci Biobehav Rev. 2016;61:108–20.

    Article  PubMed  Google Scholar 

  51. Holmlund TB, Chandler C, Foltz PW, Cohen AS, Cheng J, Bernstein JC, et al. Applying speech technologies to assess verbal memory in patients with serious mental illness. NPJ Digit Med. 2020;3:33.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bremner JD, Vythilingam M, Vermetten E, Vaccarino V, Charney DS. Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. Am J Psychiatry. 2004;161:637–45.

    Article  PubMed  Google Scholar 

  53. Green MF, Horan WP, Lee J. Social cognition in schizophrenia. Nat Rev Neurosci. 2015;16:620–31.

    Article  CAS  PubMed  Google Scholar 

  54. Meisner OC, Nair A, Chang SWC. Amygdala connectivity and implications for social cognition and disorders. Handb Clin Neurol. 2022;187:381–403.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Lesh TA, Niendam TA, Minzenberg MJ, Carter CS. Cognitive control deficits in schizophrenia: mechanisms and meaning. Neuropsychopharmacology. 2011;36:316–38.

    Article  PubMed  Google Scholar 

  56. Collier AK, Wolf DH, Valdez JN, Gur RE, Gur RC. Subsequent memory effects in schizophrenia. Psychiatry Res. 2014;224:211–7.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Eisenberg DP, Berman KF. Executive function, neural circuitry, and genetic mechanisms in schizophrenia. Neuropsychopharmacology. 2010;35:258–77.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sui J, Qi S, van Erp TGM, Bustillo J, Jiang R, Lin D, et al. Multimodal neuromarkers in schizophrenia via cognition-guided MRI fusion. Nat Commun. 2018;9:3028.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Menon V. Brain networks and cognitive impairment in psychiatric disorders. World Psychiatry. 2020;19:309–10.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Li X, Zeng J, Liu N, Yang C, Tao B, Sun H, et al. Progressive alterations of resting-state hypothalamic dysconnectivity in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2024;135:111127.

    Article  CAS  PubMed  Google Scholar 

  61. Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5:664–77.

    Article  PubMed  Google Scholar 

  62. Crossley NA, Alliende LM, Czepielewski LS, Aceituno D, Castañeda CP, Diaz C, et al. The enduring gap in educational attainment in schizophrenia according to the past 50 years of published research: a systematic review and meta-analysis. Lancet Psychiatry. 2022;9:565–73.

    Article  PubMed  Google Scholar 

  63. Ma Y, Zou Y, Liu X, Chen T, Kemp GJ, Gong Q, et al. Social intelligence mediates the protective role of resting-state brain activity in the social cognition network against social anxiety. Psychoradiology. 2024;4:kkae009.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Project Nos. 82471959, 82120108014, and 82441007), Sichuan Science and Technology Program (Grant No. 2024NSFSC1794), Institutional Research Fund from Sichuan University (No. 2023SCUH0064), 1.3.5 project for Disciplines of Excellence (Project No. ZYGD23003), West China Hospital, Sichuan University, “Qimingxing” Research Fund for Young Talents from West China Hospital of Sichuan University (Grant No. HXQMX0100).

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  1. These authors contributed equally: Xing Li, Jiaxin Zeng.

Authors and Affiliations

  1. Department of Radiology, West China Hospital of Sichuan University, Chengdu, 610041, China

    Xing Li, Jiaxin Zeng, Naici Liu, Biqiu Tang, Hui Sun, Su Lui & Wenjing Zhang

  2. Psychoradiology Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, 610041, China

    Xing Li, Jiaxin Zeng, Naici Liu, Biqiu Tang, Hui Sun, Su Lui & Wenjing Zhang

  3. Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China

    Xing Li, Jiaxin Zeng, Naici Liu, Biqiu Tang, Hui Sun, Su Lui & Wenjing Zhang

  4. Mental Health Center, West China Hospital of Sichuan University, Chengdu, 610041, China

    Changjian Qiu

  5. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, 21201, USA

    James M. Gold

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Contributions

Xing Li, Jiaxin Zeng, Su Lui and Wenjing Zhang designed the study. Xing Li, Jiaxin Zeng and Naici Liu collected and analyzed the data. Xing Li, Biqiu Tang and Hui Sun performed data visualization. Xing Li and Jiaxin Zeng drafted the manuscript. Changjian Qiu, James M. Gold, Su Lui and Wenjing Zhang reviewed and edited the manuscript. Su Lui and Wenjing Zhang provided resources and supervised the project. All authors reviewed and approved the final manuscript.

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Correspondence to Su Lui or Wenjing Zhang.

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Competing interests

Drs. Wenjing Zhang and James M. Gold consult to VeraSci. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval and consent to participate

This study includes a meta-analysis based on secondary data from previously published, publicly available data. No new human or animal participants were recruited or studied directly by the authors. This study was performed in accordance with the relevant guidelines and regulations. All studies included in the meta-analysis had received ethical approval from their respective institutional review boards, and informed consent was obtained from all participants in those original studies. Therefore, no additional ethical approval or informed consent was required for this study.

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Li, X., Zeng, J., Liu, N. et al. Functional brain abnormalities of cognitive impairments in schizophrenia indicating higher integration of working memory than other domains. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03518-2

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