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| Name | Class |
|---|---|
| IRCCS National Neurological Institute "C. Mondino" Foundation | OTHER |
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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.
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"
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Cognitive discrimination response task (DRT) | This computer-assisted task is used as an index of perceptual and cognitive control, such as inhibition, a core executive function supporting social cognition. Participants respond quickly to target stimuli and withhold responses to non-target stimuli. | 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1) |
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Inclusion Criteria for patients with cerebellar malformation include:
Inclusion Criteria for patients with degenerative cerebellar atrophy include:
Exclusion Criteria for both groups include:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Maria Leggio, MD, PhD | Contact | +39 06 49917645 | m.leggio@hsantalucia.it | |
| Renato Borgatti, MD, PhD | Contact | +39 0382 38021 | renato.borgatti@mondino.it |
| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS National Neurological Institute "C. Mondino" Foundation | Recruiting | Pavia | 27100 | Italy |
Anonymized dataset will be available at https://zenodo.org/
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Before data analyses, for ten years.
Data are publicly accessible, but files will be restricted to users with access to the repository platform.
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| 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. |
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| High-density event-related potentials (ERPs) recording | ERPs are measured during the DRT, to examine pre- and post-stimulus activity, capturing reactive sensory-motor processes, proactive motor preparation, and cognitive anticipation | 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1) |
| Cortical rhythms | EEG recordings are collected at rest (5 minutes) and during the DRT (15 minutes) to assess changes in delta, alpha, beta, and gamma power across time points, focusing on regions linked to socio-cognitive functions | 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1) |
| NEPSY-II: Social Perception | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It assesses the ability to recognize facial affect and understand mental states (Theory of Mind). | 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 | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It evaluates selective attention, inhibitory control, and cognitive flexibility. | 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: Language | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It assesses phonological awareness, verbal retrieval, and receptive language. | 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: Memory and Learning | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It measures immediate and delayed recall for both verbal and visuospatial information. | 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: Sensorimotor functions | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It evaluates fine motor coordination, finger dexterity, and visuomotor precision. | 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: Visuospatial Processing | For participants ≤16 years, a domain-specific Composite Score is calculated as the arithmetic mean of the age-standardized scaled scores (Mean=10, SD=3; range 1-19) of the administered subtests. It measures visual-perceptual analysis, orientation, and mental rotation. | 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) |
| Reading the Mind in the Eyes Test (RMET) | For participants >16 years, an advanced test of Theory of Mind and social intelligence is administered. The outcome is the total number of correctly identified mental states from photographs of the eye region. | 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) |
| Faux Pas Recognition Test | For participants >16 years, a measure of social cognition and the ability to detect social "faux pas" is administered. Outcomes include total scores for detecting, identifying, and explaining social transgressions. | 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) |
| Albert Test | For participants >16 years, a screening task for visual attention is administered. The outcome is typically reported as the number of lines crossed or a omission score, assessing spatial attention and orientation. | 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) |
| Stroop Test | For participants >16 years, a measure of selective attention and cognitive inhibition iss administered. Outcomes include completion time and error rates across three conditions (Word, Color, and Color-Word interference). | 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) |
| Token test | For participants >16 years, a measure of receptive language and oral command comprehension is administered. The outcome is the total number of correct responses (maximum score varies by version, e.g., 36 or 62). | 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) |
| Rey Auditory Verbal Learning Test (RAVLT) | For participants >16 years, an assessment of verbal learning and memory is administered. Outcomes include Immediate Recall (sum of trials 1-5), Delayed Recall (after 20-30 min), and Recognition scores. | 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) |
| Rey-Osterrieth Complex Figure | For participants >16 years, a measure of visuospatial construction and visual memory is administered. Outcomes are accuracy scores (0-36 points). | 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) |
| WAIS-IV: Block Design | For participants >16 years, a subtest measuring visuospatial organization, non-verbal reasoning, and visual-motor integration is administered. The outcome is reported as an age-standardized scaled score (Mean=10, SD=3). | 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) |
| International Cooperative Ataxia Rating Scale (ICARS) | For participants ≥ 18 years, a semi-quantitative clinical scale (0-100 points) is used to assess the severity of cerebellar ataxia. It evaluates four subdomains: posture and gait, limb coordination, speech disorders, and oculomotor disorders. Higher scores indicate greater impairment. | 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) |
| Cerebellar Cognitive Affective Syndrome Scale (CCAS) | For participants ≥ 18 years, a specialized screening tool is administered to detect cognitive and behavioral deficits associated with cerebellar lesions. It assesses executive function, linguistic processing, visuospatial abilities, and emotional regulation. | 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) |
| Vineland Adaptive Behavior Scales, Second Edition (VABS-II) | This tool is designed to assess adaptive behavior in individuals from birth to age 90 years, including open-ended questions to gather in-depth information. This scale is used to assess adaptive skills across 4 domains: communication, daily living skills, socialization and motor skills. It provides 5 scores for each domain and a total score on a 100 ± 15 distribution. | 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) |
| Coloured Progressive Matrices (CPM47) | A non-verbal measure of reasoning and fluid intelligence, consisting of 47 items requiring identification of the missing element in visual patterns. | 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) |
| I.R.C.C.S. Fondazione Santa Lucia | Not yet recruiting | Roma | 00179 | Italy |
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