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

NCT07500103 | Recruiting

• 1 other identifier: RF-2021-12374279
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Cerebellar Degeneration; Cerebellar Malformation

Keywords

Cerebellum; Social prediction; tACS; Virtual Reality

Outcome Measures

Primary Outcomes (1)

• Context-based social prediction task

  Behavioral responses (accuracy and reaction times) to three ad-hoc computer-assisted social prediction tasks and one non-social control task. The three social prediction tasks measure the ability to use contextual information to infer and predict others' mental states or traits, including action intentions, emotional states, and personality traits. All tasks share a priming-target procedure where participants select between two interpretations of a target stimulus following a congruent or incongruent situational context. Specifically, the Action Intention task requires predicting if a hand-grasp is for using or moving an object; the Emotion task involves identifying happiness or fear in facial expressions; and the Personality Trait task assesses trustworthiness judgments based on moral or immoral behaviors. A Non-social Control task requiring the classification of natural or artificial objects in indoor/outdoor environments is used as a control.

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), two months after the end of the training (t2)

Secondary Outcomes (21)

• Cognitive discrimination response task (DRT)

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1)

• High-density event-related potentials (ERPs) recording

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1)

• Cortical rhythms

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1)

• NEPSY-II: Social Perception

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), two months after the end of the training (t2)

• NEPSY-II: Attention and Executive Functioning

  1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), two months after the end of the training (t2)

Study Arms (2)

Active HD-tACS combined with IVR training

EXPERIMENTAL

At the beginning of each training session, EEG-guided active HD-tACS at the IGF will be applied for the first 20 minutes. After the stimulation, participants will be asked to report the sensations and possible side effects occurring during tACS and to rate their feelings on several visual analogue scales and Likert scales. Following the stimulation, the IVR social prediction training will be administered.

Device: EEg-guided High-Definition transcranial alternate current stimulation (HD-tACS); Behavioral: Immersive Virtual Reality (IVR) Social Prediction training

Sham HD-tACS combined with VR training

SHAM COMPARATOR

At the beginning of each training session, EEG-guided sham HD-tACS will be applied for the first 20 minutes. In this condition, after the initial 30 seconds of ramp-up phase of the current, the stimulation is switched off. This procedure allows participants to feel the characteristic tingling sensations in the vicinity of the electrodes for a brief period of time, which enhances the plausibility of blinding. After 20 minutes from setting-up the stimulation, participants will be asked to report the sensations and possible side effects occurring during tACS and to rate their feelings on several visual analogue scales and Likert scales. Following the stimulation, the IVR social prediction training will be administered.

Device: EEg-guided High-Definition transcranial alternate current stimulation (HD-tACS); Behavioral: Immersive Virtual Reality (IVR) Social Prediction training

Interventions

EEg-guided High-Definition transcranial alternate current stimulation (HD-tACS) DEVICE

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.

Active HD-tACS combined with IVR training; Sham HD-tACS combined with VR training

Immersive Virtual Reality (IVR) Social Prediction training BEHAVIORAL

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.

Active HD-tACS combined with IVR training; Sham HD-tACS combined with VR training

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented malformations confined to the cerebellum confirmed by a 3T brain MRI scan;
• Age ranging from 12 to 32 years old;
• IQ \>= 50;
• Absence of extra-cerebellar malformations on conventional brain MRI scan.
• Evidence of diffuse cerebellar atrophy;
• More than 6 months of illness;
• IQ \>=75;
• Absence of any cortical lesion on conventional brain MRI scans

You may not qualify if:

• Presence of severe motor and visual impairments, as well as neurodevelopmental (i.e., autism), neurological or psychiatric disorders that could interfere with task execution and protocol compliance;
• Presence of any contraindication for tACS.

Sponsors & Collaborators

• I.R.C.C.S. Fondazione Santa Lucia: lead
• IRCCS National Neurological Institute "C. Mondino" Foundation: collaborator

Study Sites (2)

IRCCS National Neurological Institute "C. Mondino" Foundation

Pavia, 27100, Italy

RECRUITING

I.R.C.C.S. Fondazione Santa Lucia

Roma, 00179, Italy

NOT YET RECRUITING

Study Officials

• Maria Leggio, MD, PhD

  I.R.C.C.S. Fondazione Santa Lucia

  PRINCIPAL INVESTIGATOR

• Renato Borgatti, MD, PhD

  IRCCS National Neurological Institute "C. Mondino" Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Leggio, MD, PhD

CONTACT

+39 06 49917645; m.leggio@hsantalucia.it

Renato Borgatti, MD, PhD

CONTACT

+39 0382 38021; renato.borgatti@mondino.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2026
• First Posted: March 30, 2026
• Study Start: January 15, 2025
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): April 1, 2027
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: Before data analyses, for ten years.
• Access Criteria: Data are publicly accessible, but files will be restricted to users with access to the repository platform.

Locations

IT (2)