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

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

Interventions

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.

Sponsors & Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation

  collaborator OTHER

• I.R.C.C.S. Fondazione Santa Lucia

  lead OTHER

Principal Investigators

• Maria Leggio, MD, PhD · I.R.C.C.S. Fondazione Santa Lucia

• Renato Borgatti, MD, PhD · IRCCS National Neurological Institute "C. Mondino" Foundation

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

12 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-01-15

Primary Completion

2027-02-28

Completion

2027-04-30

Countries

• Italy

Study Locations