NCT07500103

Spatiotemporal Entrainment Neuromodulation Targeting Cerebello-Cerebral Circuits to Enhance Cognitive and Social Rehabilitation in Cerebellar Diseases

Spatiotemporal Entrainment as Innovative Neuromodulation Targeting Cerebello-cerebral Circuits for Enhancing Rehabilitation Outcomes of Cognitive and Social Skills in Progressive and Acquired Cerebellar Diseases

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: I.R.C.C.S. Fondazione Santa Lucia · Academic / Other
• Sex: All
• Age: 12 Years
• Healthy volunteers: Not accepted

Summary

The cerebellum is increasingly recognized for its crucial role in high-level cognitive processes, particularly in the domain of social cognition and action prediction. Disruptions in cerebellar circuits can lead to significant impairments in anticipating others' intentions and behaviors, affecting daily social interactions. This randomized, double-blind, sham-controlled trial protocol investigates the combined effects of personalized cerebellar High-Definition transcranial Alternating Current Stimulation (HD-tACS) and Immersive Virtual Reality (IVR) training on social prediction abilities. The study involves two clinical populations: adolescents and young adults with congenital cerebellar malformations (CM) and adults with acquired neurodegenerative cerebellar atrophy (CA). Participants undergo eight daily sessions of IVR training designed to enhance internal models of social events through interactive scenarios. Simultaneously, they receive either active or sham HD-tACS delivered at their Individual Gamma Frequency (IGF), determined via baseline EEG. The primary outcomes include behavioral responses to context-based social prediction tasks (action intentions, emotions, and personality traits). Secondary outcomes encompass electrophysiological measures, neuropsychological functioning, and adaptive behavior. By integrating neuromodulation with embodied virtual experiences, the project aims to facilitate cerebello-cerebral plasticity and provide a novel transdiagnostic rehabilitative approach for socio-cognitive impairments.

Detailed description

This represents the protocol of the RCT of the project "SINCRO: Spatiotemporal entrainment as Innovative Neuromodulation targeting Cerebello-cerebral circuits for enhancing Rehabilitation Outcomes of cognitive and social skills in progressive and acquired cerebellar diseases" (Italian Ministry of Health, RF-2021-12374279). The study employs two arms of a randomized, double-blind, sham-controlled, pre-post-test trial (RCT) with 30 adolescents and young adults with congenital cerebellar malformations (CM) and 30 adults with degenerative cerebellar atrophy (CA), respectively (see Eligibility Criteria section for details). Eligible patients are contacted by medical doctors and those willing to participate are enrolled. Participants undergo eight daily (1 hour) sessions of an IVR training of social prediction abilities (see Interventions section for details), receiving either active or sham cerebellar IGF HD-tACS (see Interventions section for details). Each participant is assigned randomly to either the active or sham group in a 1:1 allocation ratio, using a computer-generated blocked randomization process carried out by independent personnel not directly engaged in the study. The intervention is carried out for 8 consecutive days for 1h/day. Patients with CM and CA are assessed before the start of treatment (T0), immediately after the end of treatment (T1) and two months after the end (T2). The overall RCT is structured as follows. In the first session prior to the beginning of the training (t0), the RCT includes the administration of all primary and secondary outcome measures (please refer to the outcome measures for a more detailed description). Among outcome measures, analyses of the cortical rhythms recorded by electroencephalogram (EEG) at rest are conducted to derive the Individualized Gamma Frequency (IGF), which is matched to each patient's specific stimulation frequency delivered through HD-tACS during the training. For each training day, the treatment lasts one hour. During the first 20 minutes of treatment the active or sham HD-tACS (according to the group allocation) is delivered. After the end of the stimulation, patients are asked to rate the sensations experienced during the stimulation through Visual Analogue Scales and through child-friendly Likert scales. Then, they perform the IVR social prediction training for the remaining session time without stimulation. Soon after the end of all the training sessions, patients carry out the T1 evaluation. As for the T0 session, this session includes the administration of all primary and secondary outcome measures. Two months after the end of the training (T2) all primary and secondary outcome measures, except for resting and task-related EEG recordings, are administered. Primary outcomes will include the behavioural responses to three computer-assisted, context-based social prediction tasks and a non-social control task. Secondary outcomes include electrophysiological measures of anticipatory control, perception, and attention, cortical rhythms, neuropsychological tests, as well as scales for adaptive behavior, and fluid intelligence. Staff conducting pre/post assessments, personnel leading the IVR training and researchers analyzing data are blinded, whereas the personnel administering the stimulation and the project administrators are not. The personnel administering the stimulation is the only person in the room aware of the correspondence between a specific code and stimulation protocol and leaves when the stimulation (either active or sham) is over, thus preventing any influence on training administration. Of note, the electrode placement procedure is identical for both sham and active stimulation conditions, which helps maintain blinding of both participants and study personnel to treatment allocation, ensuring that the personnel conducting the training remain unaware of the treatment allocation. Unblinding should only occur in rare cases where knowledge of the treatment is crucial for managing the patient, such as in the case of adverse events. The intervention takes place at IRCCS Mondino Foundation (Pavia) for CM patients and at IRCCS Santa Lucia Foundation (Rome) for CA patients. This trial is supported by the Italian Ministry of Health, project RF-2021-12374279 "SINCRO: Spatiotemporal entrainment as Innovative Neuromodulation targeting Cerebello-cerebral circuits for enhancing Rehabilitation Outcomes of cognitive and social skills in progressive and acquired cerebellar diseases"

Conditions

• Cerebellar Degeneration
• Cerebellar Malformation

Interventions

Type	Name	Description
DEVICE	EEg-guided High-Definition transcranial alternate current stimulation (HD-tACS)	EEG-guided HD-tACS is delivered via a CE-marked Starstim® 8-channel device using a multifocal montage with the active ring electrode centered over the left cerebellar hemisphere (2 cm below and 3 cm left of the inion) and four equidistant references (4 cm). This configuration, validated by SimNIBS 4.1 electric field modeling, targets cerebellar regions linked to mentalizing connectivity. Stimulation is applied for 20 minutes daily at 1 mA peak-to-peak intensity-selected for its safety and efficacy in younger participants-including 30-second ramp-up/down phases. In the sham condition, current is deactivated after the initial ramp-up to maintain blinding through transient tingling. The stimulation frequency is individually tailored to each participant's Individual Gamma Frequency (IGF), identified as the peak power within the 30-80 Hz band via Welch's PSD estimation of 19-channel EEG data (10/10 system) recorded at 500 Hz and processed using FIR filtering.
BEHAVIORAL	Immersive Virtual Reality (IVR) Social Prediction training	The protocol employs age-matched, immersive virtual scenarios developed in Blender and Unity, delivered via Meta Quest 2 HMD (120 Hz, 110° FOV) to ensure a high sense of presence. To maximize ecological validity through personalized settings, adolescents interact with school-based environments (library/playground), while adults use a supermarket or restaurant. From a first-person perspective with synchronous hand-tracking, participants observe three objects on a counter as an avatar approaches. Each session (40 mins) includes 88 trials where participants must infer and predict the avatar's preferred object category (e.g., beverages, books) and grasp it first. Three avatars follow specific preferences, while a fourth acts randomly; mappings are pseudo-randomized across eight sessions to ensure identity-based learning. Feedback is provided via auditory cues.

Timeline

• Start date: 2025-01-15
• Primary completion: 2027-02-01
• Completion: 2027-04-01
• First posted: 2026-03-30
• Last updated: 2026-03-30

Locations

2 sites across 1 country: Italy