Effects of Cerebellar tACS-iTBS in Ataxia

Official title

Effects of Combined Transcranial Electrical and Magnetic Stimulation of Cerebellum on Balance Function in Ataxia Patients

Overview

Ataxia refers to a group of neurological disorders characterized by impaired coordination and balance due to dysfunction in the cerebellum or its connections. Traditional therapeutic approaches for ataxia have shown limited efficacy, prompting researchers to explore alternative interventions. Non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and intermittent theta burst stimulation (iTBS), have emerged as potential therapeutic options. The aim of this study is to investigate the combined effect of tACS-iTBS on balance functions in ataxia disorders.

Detailed description

Ataxia comprises a heterogeneous group of acquired or inherited disorders primarily involving cerebellar dysfunction, leading to impaired coordination and motor learning. Traditional treatments, including medication and physical therapy, often provide limited symptomatic improvement. Non-invasive brain stimulation (NIBS) techniques have emerged as promising tools for modulating cerebellar activity and enhancing motor function. Transcranial magnetic stimulation (TMS) can influence cortical excitability and plasticity, and studies have shown that high-frequency cerebellar rTMS can improve motor performance in spinocerebellar ataxia. Intermittent theta burst stimulation (iTBS), a patterned form of TMS, has demonstrated benefits in other movement disorders, suggesting potential applicability to ataxia. Transcranial direct current stimulation (tDCS), which modulates neuronal excitability via weak electrical currents, has shown improvements in static and dynamic balance in degenerative cerebellar ataxia. Transcranial alternating current stimulation (tACS) modulates neural oscillations and early studies indicate possible benefits for ataxia symptoms. Recent work has explored combining NIBS modalities to enhance neuromodulatory effects. In preliminary experiments, combined cerebellar tACS and iTBS increased MEP amplitudes more than iTBS alone, with effects lasting up to 30 minutes. These synergistic effects may translate into improved motor performance, coordination, and balance. The present study aims to investigate whether combining real or sham tACS with iTBS produces greater benefits than exergaming biofeedback alone in individuals with ataxia. A cross-over design will be used so that each participant serves as their own control. The primary outcomes will include motor coordination, balance, and cerebello-cortical plasticity. The rationale is that tACS may optimize oscillatory activity while iTBS enhances excitability, thereby jointly promoting neuroplasticity in cerebellar networks. The study will recruit individuals diagnosed with ataxia and assess the therapeutic potential of combined NIBS interventions.

Interventions

• Device Real (real iTBS/tACS + exergaming)
  Stimulation will be applied to the cerebellum. The tACS session duration will be 190 seconds with a frequency of 5 Hz coupled with iTBS (coil positioned tangentially with respect to the scalp)(600 pulses consisting of bursts of 3 stimuli at 50 Hz, repeated at intervals of 200ms, with an intensity of 80% of active motor threshold -AMT-) (Huang et al., 2005) for a total duration of 190 seconds (repeated over both cerebellar hemispheres after a 15-minute rest period). The exergaming will be perform
• Device Sham (sham iTBS/tACS + exergaming)
  Stimulation will be applied to the cerebellum. The tACS session duration will be 10 seconds with a frequency of 5 Hz coupled with sham iTBS (coil positioned perpendicularly with respect to the scalp)(600 pulses consisting of bursts of 3 stimuli at 50 Hz, repeated at intervals of 200ms, with an intensity of 80% of active motor threshold -AMT-) (Huang et al., 2005) for a total duration of 190 seconds (repeated over both cerebellar hemispheres after a 15-minute rest period). The exergaming will be

Primary outcome measures

• Changes in the International Cooperative Ataxia Rating Scale (ICARS) [Time frame: Baseline (1), 2 weeks from baseline (1), Baseline (2), 2 weeks from baseline (2)]

Secondary outcome measures (4)

• Changes in the Short Form-36 Health Survey (SF-36) [Time frame: Baseline (1), 2 weeks from baseline (1), Baseline (2), 2 weeks from baseline (2)]
• Changes in postural control [Time frame: Baseline (1), 2 weeks from baseline (1), Baseline (2), 2 weeks from baseline (2)]
• Changes in cortico-spinal excitability [Time frame: Baseline (1), 2 weeks from baseline (1), Baseline (2), 2 weeks from baseline (2)]
• Change in the Scale for the Assessment and Rating of Ataxia (SARA) [Time frame: Baseline (1), 2 weeks from baseline (1), Baseline (2), 2 weeks from baseline (2)]

Eligibility criteria

Inclusion criteria

• Confirmed diagnosis of ataxia based on clinical assessment and/or neuroimaging findings.
• Stable medication regimen for at least four weeks prior to the study.
• Sufficient cognitive ability to understand and comply with study instructions.

Exclusion criteria

• History of seizures.
• Severe general impairment or concomitant diseases.
• Intracranial metal implants.
• Cardiac pacemaker.
• Pregnancy status.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Santa Lucia Foundation — Rome

Publications

• Spampinato D, Avci E, Rothwell J, Rocchi L. Frequency-dependent modulation of cerebellar excitability during the application of non-invasive alternating current stimulation. Brain Stimul. 2021 Mar-Apr;14(2):277-283. doi: 10.1016/j.brs.2021.01.007. Epub 2021 Jan 20. PMID 33482375
• Libri I, Cantoni V, Benussi A, Rivolta J, Ferrari C, Fancellu R, Synofzik M, Alberici A, Padovani A, Borroni B. Comparing Cerebellar tDCS and Cerebellar tACS in Neurodegenerative Ataxias Using Wearable Sensors: A Randomized, Double-Blind, Sham-Controlled, Triple-Crossover Trial. Cerebellum. 2024 Apr;23(2):570-578. doi: 10.1007/s12311-023-01578-6. Epub 2023 Jun 22. PMID 37349632
• Guerra A, Suppa A, Bologna M, D'Onofrio V, Bianchini E, Brown P, Di Lazzaro V, Berardelli A. Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation. Brain Stimul. 2018 Jul-Aug;11(4):734-742. doi: 10.1016/j.brs.2018.03.015. Epub 2018 Mar 24. PMID 29615367
• Gong C, Long Y, Peng XM, Hu H, Chen J, Xiao L, Zhong YB, Wang MY, Luo Y. Efficacy and safety of noninvasive brain stimulation for patients with cerebellar ataxia: a systematic review and meta-analysis of randomized controlled trials. J Neurol. 2023 Oct;270(10):4782-4799. doi: 10.1007/s00415-023-11799-8. Epub 2023 Jul 17. PMID 37460852
• Spampinato DA, Pezzopane V, Cinnera AM, D'Arienzo M, Piatti D, Ferraresi M, Vinci AC, Colona VL, Vasco G, Grasso MG, Paolucci S, Bonni S, Koch G. Effects of combined cerebellar tACS-iTBS in individuals with ataxia (EtABeta): a crossover investigation. Trials. 2026 Mar 24;27(1):346. doi: 10.1186/s13063-026-09653-z. PMID 41877266

Identifiers

NCT: NCT06420271 · 80/SL/23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗