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Cited by 70Transcranial Magnetic Stimulation StudiesSchizophrenia research and treatmentElectroconvulsive Therapy Studies

Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial

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Basavaraju, Rakshathi, Ithal, Dhruva, Thanki, Milind Vijay, Ramalingaiah, Arvinda Hanumanthapura, Thirthalli, Jagadisha, Reddy, Rajakumari P., Brady, Roscoe O., Halko, Mark A. +5 more·2021·Schizophrenia Research
DOI 10.1016/j.schres.2021.10.005PMC PMC8662658
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Abstract

Objective Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. Methods Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). Results Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (p cluster-FWER = 0.033), right pallidum (p cluster-FWER = 0.042) and right frontal pole (p cluster-FWER = 0.047) in the real arm with no change in the sham arm. Conclusion Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.

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  • In subjects with schizophrenia, CBM-iTBS positively impacts affective and cognitive symptoms.

    “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 Basavaraju et al., 2021

    The Results (Mixed Models Repeated Measures analysis; page unavailable) report that cognitive measures improved over time in both the real and sham groups, with no significant difference between them on clinical or cognitive changes. The Discussion likewise states that real stimulation did not significantly outperform sham stimulation on negative or cognitive symptoms. Thus this trial does not show the attributed positive effect of CBM-iTBS on affective and cognitive symptoms. (LLM, conf=0.86)

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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 Basavaraju et al., 2021

    The Results (rsfMRI; page not provided) report increased cerebellar–frontal functional connectivity after real iTBS in participants with schizophrenia, although the change did not differ significantly from sham. The paper does not report a brain-metabolism outcome, so that part of the claim is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Other TMS depression trials have experienced similarly robust placebo responses, including CBM-iTBS trials.

    “Other TMS depression trials have experienced similarly robust placebo responses, including CBM-iTBS trials (Basavaraju et al., 2021; Chauhan 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 Basavaraju et al., 2021

    The Results and Discussion (page not available in our copy) report improvement in both real and sham cerebellar iTBS arms and describe a high placebo response. But this was a trial in people with schizophrenia and predominant negative symptoms, not a TMS depression trial; the Discussion says participants had minimal or absent depressive symptoms. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Other studies suggest a prominent placebo effect for CBM-iTBS.

    “However, other studies suggest a prominent placebo effect (Basavaraju 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 Basavaraju et al., 2021

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1 of the 89 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Huang Y-Z Edwards MJ Rounis E Bhatia KP Rothwell JC Theta burst stimulation of the human motor cortex Neuron 2005a 45 201 206 15664172

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Authors
Basavaraju, R., Ithal, D., Thanki, M. V., Ramalingaiah, A. H., Thirthalli, J., Reddy, R. P., Brady, R. O., Halko, M. A., Bolo, N. R., Keshavan, M. S., Pascual-Leone, A., Mehta, U. M., & Kesavan, M.
Affiliations
  • National Institute of Mental Health and Neurosciences (IN)
  • Beth Israel Deaconess Medical Center (US)
  • Harvard University (US)
Corresponding author
  • Mehta, Urvakhsh Meherwan
  • Kesavan, Muralidharan
ORCID
Venue
Schizophrenia Research
Publisher
Elsevier BV
Published
2021-12
Volume
238
Pages
108-120
ISSN
0920-9964 (ISSN-L)
DOI
10.1016/j.schres.2021.10.005
PMC
PMC8662658
OpenAlex
W3205354993
Cited by
70
References
89
Citations by year
2026: 10 · 2025: 18 · 2024: 22 · 2023: 9 · 2022: 10 · 2021: 1
FWCI
4.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Schizophrenia Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust
  • Department of Biotechnology, Ministry of Science and Technology, India
  • The Wellcome Trust DBT India Alliance (IA/RTF/15/1/1009, IA/RTF/15/1/1004, R01 MH116170)
Topics
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Keywords
intermittent theta burst stimulation, cerebellar vermis
MeSH terms
Cerebellum, Humans, Schizophrenia, Prefrontal Cortex, Transcranial Magnetic Stimulation, Cerebellar Vermis

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