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Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk
Open accessAbstract
Background Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. Results In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.
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“Schizophrenia is associated with accelerated gray matter loss in PFC (Cannon, Chung, He, Sun, Jacobson, van Erp, & Consortium, 2014), including loss of dendrites and spines in the dlPFC (Glantz & Lewis, 2000).”
From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Cannon et al., 2014
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“For example, there is loss of dlPFC gray matter in schizophrenia4,5 and Alzheimer’s disease6, while changes in more ventral and medial PFC regions are evident in mood disorders7 and in post-traumatic-stress disorder (PTSD)8.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [5]
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“Indeed, the onset of schizophrenia is accompanied by waves of PFC gray matter loss, as well as increased signs of inflammation5.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [5]
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“Indeed, the onset of schizophrenia is accompanied by waves of PFC gray matter loss, as well as increased signs of inflammation5.”
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“As guanfacine is approved by the US Food and Drug Administration for use in adolescents103, it may offer a practical approach for reducing the inflammatory response and gray matter loss found in prodromal schizophrenia5.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [5]
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Reduced visual scanpath is associated with inferential reasoning task in schizophrenia
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Vasiliu, O., Marinescu, I. P., Mangalagiu, A. G., Petrescu, B. M., & Ciobanu, A. M. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15207955
Metadata
- Authors
- Cannon, T. D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T. G. M., McEwen, S., Addington, J., Bearden, C. E., Cadenhead, K., Cornblatt, B., Mathalon, D. H., McGlashan, T., Perkins, D., Jeffries, C., Seidman, L. J., Tsuang, M., Walker, E., Woods, S. W., & Heinssen, R.
- Affiliations
- Yale University (US)
- University of California, Los Angeles (US)
- University of California, Irvine (US)
- University of Calgary (CA)
- University of California San Diego (US)
- Zucker Hillside Hospital (US)
- University of California, San Francisco (US)
- University of North Carolina at Chapel Hill (US)
- Beth Israel Deaconess Medical Center (US)
- Emory University (US)
- National Institute of Mental Health (US)
- Corresponding author
- Cannon, Tyrone D.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 77
- Issue
- 2
- Pages
- 147-157
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4264996
- OpenAlex
- W2166663076
- Cited by
- 599
- References
- 63
- Citations by year
- 2026: 28 · 2025: 28 · 2024: 38 · 2023: 49 · 2022: 44 · 2021: 73 · 2020: 73 · 2019: 78 · 2018: 38 · 2017: 43 · 2016: 54 · 2015: 44
- FWCI
- 37.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Commonwealth of Massachusetts
- National Institute of Mental Health
- National Institutes of Health (MH081902, MH066160, MH081928, MH081857, MH082004, P50 MH080272, MH081988, P50 MH066286, MH082022, MH081984)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- clinical high risk for psychosis, transition to psychosis, cortical thickness, gray matter loss, schizophrenia pathophysiology, inflammatory cytokines, frontal cortex, prodromal symptoms, youth
- MeSH terms
- Adolescent, Cerebral Cortex, Female, Follow-Up Studies, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Organ Size, Psychotic Disorders, Risk, Antipsychotic Agents, Reproducibility of Results, Cytokines, Disease Progression, Young Adult, Prodromal Symptoms
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