Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia
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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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In subjects with schizophrenia, CBM-iTBS can alter brain metabolism and cerebellar-frontal functional connectivity.
“In subjects with schizophrenia, CBM-iTBS can alter brain metabolism and cerebellar-frontal functional connectivity (Basavaraju et al., 2021; Brady et al., 2019; Cho et al., 2012; Halko et al., 2014; Singh et al., 2019), as well as positively impact affective and cognitive symptoms (Basavaraju et al., 2021; Demirtas-Tatlidede et al., 2010; Garg et al., 2016; Shinn et al., 2023; Zhu et al., 2021).”
From A double-blind, randomized, sham-controlled clinical trial of cerebellar intermittent theta burst stimulation for bipolar disorder: Safety, tolerability, mood and cognitive effects (2025) · cites this paper as Brady et al., 2019
The Results (Network Validation with TMS; page unavailable) report that cerebellar intermittent theta-burst stimulation increased cerebellar–dorsolateral prefrontal functional connectivity more than sham stimulation in participants with schizophrenia. Our copy does not report a change in brain metabolism, so that part of the attributed claim is unsupported. (LLM, conf=0.90)
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Self-citation
- 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
- Venue
- American Journal of Psychiatry
- Published
- 2019-07-01
- Volume
- 176
- Issue
- 7
- Pages
- 512-520
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- 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 · 2018: 1
- 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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