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Neighborhood social fragmentation in relation to impaired mismatch negativity among youth at clinical high risk for psychosis and healthy comparisons

Neuropsychopharmacology volume 50, pages 1446–1454 (2025)Cite this article

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Abstract

Impairments in mismatch negativity (MMN) are well-established in schizophrenia and have been observed in youth at clinical high-risk for psychosis (CHR-P). Prior animal studies have shown that social isolation may be related to neurobiological changes, including reduced MMN-like responses and schizophrenia-like behaviors. In parallel, neighborhood social fragmentation has been shown to be associated with the onset of psychosis. This study investigates the association between neighborhood social fragmentation and MMN impairment among CHR-P youth and healthy comparisons (HC). Data were collected from the North American Prodrome Longitudinal Study Phase 2. Electroencephalography was recorded during an unattended auditory oddball paradigm with duration-, pitch-, and double-deviant tones. Generalized linear mixed models tested the association between neighborhood social fragmentation and the frontal-central averaged MMN for three deviant types for youth at CHR-P and HC separately. The models adjusted for age, sex, race/ethnicity, parental education, parental history of psychosis, and neighborhood poverty. Participants (mean [SD] age: 18.69 [4.59], 41.9% females, 51.3% White non-Hispanic) included 304 CHR-P and 92 HC. In the CHR-P group, greater neighborhood social fragmentation was associated with impaired duration-deviant MMN (bootstrapped β = 0.18, 95% CI: 0.04 to 0.33, p = .022) but not for pitch-deviant (bootstrapped β = 0.09, 95% CI: −0.05 to 0.22, p = .199) or double-deviant MMN (bootstrapped β = 0.10, 95% CI: −0.09 to 0.17, p = .559). Greater neighborhood social fragmentation was associated with impaired duration-deviant MMN amplitude among high-risk individuals. Further research is needed to explore underlying mechanisms.

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Fig. 1: Mismatch negativity amplitude by social fragmentation index among CHR-P individuals (n = 304).
Fig. 2: Associations between social fragmentation index and duration-deviant MMN in CHR-P and HC subgroup.

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Data availability

All NAPLS-2 data are available upon request from the study authors.

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Funding

This work was supported in part by the National Institute of Mental Health (NIMH) grants U01 MH081902 to TDC, P50 MH066286 to CEB, U01 MH081857 to BAC, U01 MH82022 to SWW, U01 MH066134 to JA, U01 MH081944 to KSC, R01 U01 MH066069 to DOP, R01 MH076989 to DHM, U01 MH081988 to EW, and K23 MH129684 to BSK. ED, HH, DHM, GAL, and MAN are employees of the US government. The content is solely the responsibility of the authors and does not necessarily reflect the position or policy of the National Institutes of Health, the Department of Veterans Affairs, or the US government.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    Benson S. Ku, Qingyue Yuan & Erica Duncan

  2. Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA

    Holly Hamilton

  3. Minneapolis Veteran Affairs Health Care System, Minneapolis, MN, USA

    Holly Hamilton

  4. Department of Psychiatry & Behavioral Sciences, University of California, San Francisco, CA, USA

    Holly Hamilton & Daniel H. Mathalon

  5. Departments of Psychology, Emory University, Atlanta, GA, USA

    David A. Parker & Elaine Walker

  6. San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA

    Brian J. Roach & Daniel H. Mathalon

  7. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Peter M. Bachman

  8. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Aysenil Belger & Diana O. Perkins

  9. Division of Psychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY, USA

    Ricardo E. Carrión & Barbara A. Cornblatt

  10. Institute of Behavioral Science, Feinstein Institutes of Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA

    Ricardo E. Carrión

  11. Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Ricardo E. Carrión & Barbara A. Cornblatt

  12. Atlanta Veterans Affairs Health Care System, Decatur, GA, USA

    Erica Duncan

  13. Department of Psychiatry, Yale University, New Haven, CT, USA

    Jason K. Johannesen, Tyrone D. Cannon & Scott W. Woods

  14. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Gregory A. Light & Kristin S. Cadenhead

  15. Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA

    Gregory A. Light

  16. Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center, Boston, MA, USA

    Margaret A. Niznikiewicz, Matcheri Keshavan & William Stone

  17. Veterans Affairs Boston Healthcare System, Brockton, MA, USA

    Margaret A. Niznikiewicz

  18. Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Jean Addington

  19. Departments of Psychiatry and Biobehavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA

    Carrie E. Bearden

  20. Department of Psychology, Yale University, New Haven, CT, USA

    Tyrone D. Cannon

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Contributions

The authors confirm their contributions to the paper as follows: Study Conception and Design: BK, HH, QY, EW, DM; Data Collection: BK, HH, QY, DP, BR, PB, AB, RC, ED, JJ, GL, MN, JA, CB, KC, TC, MK, DP, WS, SW, EW, DM; Analysis and Interpretation of Results: BK, HH, QY, CB, EW, DM; Drafting of the Original Manuscript: BK, HH, QY; Critical Revision for Important Intellectual Content: BK, HH, QY, DP, BR, PB, AB, RC, ED, JJ, GL, MN, JA, CB, KC, TC, MK, DP, WS, SW, EW, DM. All authors reviewed the results, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Benson S. Ku.

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Competing interests

TDC has served as a consultant for Boehringer-Ingelheim Pharmaceuticals and Lundbeck A/S. DOP has served as a consultant for Sunovion and Alkermes, has received research support from Boehringer-Ingelheim, and has received royalties from American Psychiatric Association Publishing. SWW has received investigator-initiated research support from Pfizer and sponsor-initiated research support from Auspex and Teva; he has served as a consultant for Biomedisyn (unpaid), Boehringer-Ingelheim, and Merck and as an unpaid consultant to DSM-5; he has been granted a patent for a method of treating prodromal schizophrenia with glycine; and he has received royalties from Oxford University Press. ED has received research support for work unrelated to this project from Posit Science Inc, Auspex Pharmaceuticals, Teva Pharmaceuticals, and GrayMatters Health. The other authors report no financial relationships with commercial interests.

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Ku, B.S., Hamilton, H., Yuan, Q. et al. Neighborhood social fragmentation in relation to impaired mismatch negativity among youth at clinical high risk for psychosis and healthy comparisons. Neuropsychopharmacol. 50, 1446–1454 (2025). https://doi.org/10.1038/s41386-025-02093-4

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