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

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

Status: Enrolling

Conditions: Cerebellar Degeneration; Cerebellar Malformation

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

Study type: Interventional

Funder types: Other

Identifiers

NCT07500103

RF-2021-12374279

Details and patient eligibility

About

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.

Full 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"

Enrollment: 60 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for patients with cerebellar malformation include:

• 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.

Inclusion Criteria for patients with degenerative cerebellar atrophy include:

• Evidence of diffuse cerebellar atrophy;
• More than 6 months of illness;
• IQ >=75;
• Absence of any cortical lesion on conventional brain MRI scans

Exclusion Criteria for both groups include:

• 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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60 participants in 2 patient groups

Active HD-tACS combined with IVR training

Experimental group

Description:

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.

Treatment:

Behavioral: Immersive Virtual Reality (IVR) Social Prediction training

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

Sham HD-tACS combined with VR training

Sham Comparator group

Description:

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.

Treatment:

Behavioral: Immersive Virtual Reality (IVR) Social Prediction training

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