Cited by 372Functional Brain Connectivity StudiesSchizophrenia research and treatmentTranscranial Magnetic Stimulation Studies

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Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia

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Brady, Roscoe O., Gonsalvez, Irene, Lee, Ivy, Öngür, Dost, Seidman, Larry J., Schmahmann, Jeremy D., Eack, Shaun M., Keshavan, Matcheri S., Pascual-Leone, Alvaro, Halko, Mark A.·2019·American Journal of Psychiatry

DOI 10.1176/appi.ajp.2018.18040429PMC PMC6760327

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Abstract

OBJECTIVE: The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms. METHODS: In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline. RESULTS: A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change. CONCLUSIONS: These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.

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Authors: Brady, R. O., Gonsalvez, I., Lee, I., Öngür, D., Seidman, L. J., Schmahmann, J. D., Eack, S. M., Keshavan, M. S., Pascual-Leone, A., & Halko, M. A.
Affiliations: Beth Israel Deaconess Medical Center (US)
From the Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston (Brady, Lee, Seidman, Keshavan); the Schizophrenia and Bipolar Disorders Program, McLean Hospital, Belmont, Mass. (Brady, Öngür); Harvard Medical School, Boston (Brady, Öngür); St. Elizabeth’s Medical Center, Boston (Gonsalvez); the Department of Neurology, Ataxia Unit, Cognitive Behavioral Neurology Unit, and Laboratory for Neuroanatomy and Cerebellar Neurobiology, Massachusetts General Hospital...
Corresponding author: Halko, Mark A.
ORCID: Brady, Roscoe O.
Lee, Ivy
Seidman, Larry J.
Schmahmann, Jeremy D.
Eack, Shaun M.
Keshavan, Matcheri S.
Halko, Mark A.
Venue: American Journal of Psychiatry
Publisher: American Psychiatric Association Publishing
Published: 2019-07-01
Volume: 176
Issue: 7
Pages: 512-520
ISSN: 0002-953X (ISSN-L)
1535-7228
DOI: 10.1176/appi.ajp.2018.18040429
PMC: PMC6760327
OpenAlex: W2913822739
Cited by: 372
References: 44
Citations by year: 2026: 27 · 2025: 51 · 2024: 62 · 2023: 53 · 2022: 58 · 2021: 59 · 2020: 47 · 2019: 14
FWCI: 25.87
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: American Journal of Psychiatry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Sidney R. Baer, Jr. Foundation
National Institute of Mental Health (K23MH100623, K24MH104449, R01MH111868, R01MH092440)
National Center for Research Resources (UL1RR025758)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords: schizophrenia, negative symptoms, cerebellum, dorsolateral prefrontal cortex, resting-state functional connectivity, transcranial magnetic stimulation, anhedonia, amotivation
MeSH terms: beta-Lactamases, Cerebellum, Female, Humans, Male, Models, Biological, Nerve Net, Psychiatric Status Rating Scales, Schizophrenia, Severity of Illness Index, Prefrontal Cortex, Transcranial Magnetic Stimulation, Young Adult, Neuroimaging

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Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia

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