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

Basavaraju, Rakshathi; Ithal, Dhruva; Thanki, Milind Vijay; Ramalingaiah, Arvinda Hanumanthapura; Thirthalli, Jagadisha; Reddy, Rajakumari P.; Brady, Roscoe O.; Halko, Mark A.; Bolo, Nicolas R.; Keshavan, Matcheri S.; Pascual‐Leone, Álvaro; Mehta, Urvakhsh Meherwan; Muralidharan, Kesavan

doi:10.1016/j.schres.2021.10.005

Cited by 41 publications

(48 citation statements)

References 80 publications

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“…This meta-analysis included 13 studies in which iTBS was used to treat patients with schizophrenia ( Chen et al, 2011 ; Kazemi et al, 2012 ; Zheng et al, 2012 ; Zhao et al, 2014 ; Zhen et al, 2015 ; Zhu et al, 2019 ; Walther et al, 2020 ; Wang et al, 2020 ; Basavaraju et al, 2021 ; Bation et al, 2021 ; Chauhan et al, 2021 ; Wu et al, 2021 ; Zhu et al, 2021 ). The included studies were published between 2011 and 2021.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and safety of intermittent theta-burst stimulation in patients with schizophrenia: A meta-analysis of randomized sham-controlled trials

Goh

Chen²,

Wu³

et al. 2022

Front. Pharmacol.

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Theta-burst stimulation is a non-invasive brain stimulation technique that was introduced as a potential augmentation treatment for patients with schizophrenia. The purpose of this meta-analysis was to investigate the therapeutic efficacy and safety of intermittent theta-burst stimulation in patients with schizophrenia. Following the PRISMA guidelines, the MEDLINE, Embase, Cochrane, Scopus, Web of Science, and CNKI databases were searched for relevant studies from database inception to 9 January 2022. Change in symptom severity among patients with schizophrenia was the primary outcome, and changes in cognitive function and safety profiles, including the discontinuation rate and adverse events, were secondary outcomes. In total, 13 double-blind randomized sham-controlled trials with 524 patients were included. Intermittent theta-burst stimulation adjunct to antipsychotics was associated with significantly improved psychopathology in patients with schizophrenia, particularly for negative symptoms and general psychopathology but not for positive symptoms or cognitive function. The stimulation parameters influenced the effectiveness of intermittent theta-burst stimulation. A more favorable effect was observed in patients who received theta-burst stimulation at the left dorsolateral prefrontal cortex, with ≥1800 pulses per day, for ≥20 sessions, and using an inactive sham coil as a placebo comparison in the study. The intermittent theta-burst stimulation is well tolerated and safe in patients with schizophrenia. Intermittent theta-burst stimulation adjunct to antipsychotics treatment is associated with significant improvement in negative symptoms and favorable tolerability in patients with schizophrenia. This meta-analysis may provide insights into the use of intermittent theta-burst stimulation as an additional treatment to alleviate the negative symptoms of schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Efficacy and safety of intermittent theta-burst stimulation in patients with schizophrenia: A meta-analysis of randomized sham-controlled trials

Goh

Chen²,

Wu³

et al. 2022

Front. Pharmacol.

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“…More specifically, participants who received active iTBS had significant negative symptoms reductions compared to those who received sham. Although other iTBS studies found significant improvements in negative symptoms for both the active and sham conditions ( 82 , 90 ). Studies that included only an active stimulation arm reported decreases in negative symptoms (tDCS, rtMS, or iTBS) ( 84 , 86 – 88 ), with evidence that these effects were maintained for as long as 24 weeks ( 84 , 88 ).…”

Section: Resultsmentioning

confidence: 72%

“…Nine studies examined the impact on positive symptoms. Three studies observed non-specific iTBS effects on positive symptoms, with significant reductions for participants in the active and control study arms ( 82 , 83 , 90 ). Studies with only an active stimulation arm (rTMS, iTBS, or tDCS) reported mixed results, with some finding no change ( 86 , 87 ), others finding a reduction ( 84 , 88 , 91 ), and one case study noting an increase ( 92 ) in positive symptoms.…”

Section: Resultsmentioning

confidence: 99%

Cerebellar stimulation in schizophrenia: A systematic review of the evidence and an overview of the methods

2022

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BackgroundCerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. Here we conducted an updated systematic review examining the literature on cerebellar stimulation efficacy and tolerability for mitigating symptoms of schizophrenia. We discuss the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population.MethodsTwo independent authors identified 20 published studies (7 randomized controlled trials, 7 open-label studies, 1 pilot study, 4 case reports, 1 preclinical study) that describe the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022 were identified from a search within PubMed, Scopus, and PsycInfo.ResultsMost studies stimulating the cerebellum used transcranial magnetic stimulation or transcranial direct-current stimulation, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, we did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appear tolerable for individuals with schizophrenia, with only mild and temporary side effects.ConclusionCerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlight the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022346667].

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“…Early onset schizophrenia patients have been shown to have poorer clinical and functional outcomes (Clemmensen et al, 2012; Coulon et al, 2020; Remschmidt & Theisen, 2012), and severity of negative symptoms has been found to be the most replicated predictor of worse outcomes (Díaz‐Caneja et al, 2015). With a recent emphasis on the use of iTBS as a novel biological therapeutic modality for the treatment of negative symptoms of schizophrenia (Basavaraju et al, 2021; Bodén et al, 2021; Zhu et al, 2021), our results might have significant implications for its use of in adolescents with early onset schizophrenia. Our study found a greater inhibitory and a lower excitatory cortical plasticity response in adolescents with early onset schizophrenia, implying neuronal hypoplasticity (a blunted LTP‐like response and an exaggerated LTD‐like response).…”

Section: Discussionmentioning

confidence: 84%

Motor cortical plasticity in adolescents with early onset schizophrenia: A TMS‐EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation

Purushotham

Goyal

Sinha

et al. 2022

Intl J of Devlp Neuroscience

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Background Neuroplasticity in adolescents is distinct from that of adults. Literature pertaining to neuroplasticity in schizophrenia is limited to adult populations. Aim We aimed to assess baseline (or resting) cortical excitability and cortical plasticity in adolescents with schizophrenia using the transcranial magnetic stimulation‐electromyography (TMS‐EMG) protocol. Methods Twenty adolescent cases with schizophrenia and 20 age and gender matched healthy controls were studied using a crossover design. Single pulse TMS elicited resting motor threshold (RMT) and motor evoked potentials (MEPs) were assessed. Cortical plasticity was determined by tracking MEPs after a single session continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) up to 120 min at 12 intervals. Results Baseline (or resting) cortical excitability was found to be significantly lower in cases compared with controls. Response patterns to cTBS and iTBS were similar between the crossover. While cTBS led to inhibitory response, iTBS had an excitatory effect in both the groups. In the cases, while cTBS led to significantly greater initial inhibitory response, iTBS led to significantly lower excitatory response, compared with controls. The time taken to return to baseline excitability was significantly longer after receiving cTBS for cases, compared with controls. Conclusions iTBS and cTBS lead to excitatory and inhibitory response, representing classical long‐term depression and long‐term potentiation effects, respectively, in both cases and controls. We conclude that adolescents with schizophrenia have significantly lower baseline (resting) cortical excitability as well as significantly greater inhibitory plasticity; excitatory plasticity is significantly lower.

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

Cited by 41 publications

References 80 publications

Efficacy and safety of intermittent theta-burst stimulation in patients with schizophrenia: A meta-analysis of randomized sham-controlled trials

Efficacy and safety of intermittent theta-burst stimulation in patients with schizophrenia: A meta-analysis of randomized sham-controlled trials

Cerebellar stimulation in schizophrenia: A systematic review of the evidence and an overview of the methods

Motor cortical plasticity in adolescents with early onset schizophrenia: A TMS‐EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation

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