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

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"

• Cognitive discrimination response task (DRT) [Срок оценки: 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 [Срок оценки: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1)]
• Cortical rhythms [Срок оценки: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1)]
• NEPSY-II: Social Perception [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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)]