Transcranial Alternating Current Stimulation in Cerebral Palsy (BOOSTTACS) (BOOSTTACS)

• ClinicalTrials.gov Identifier: NCT06372041
• Recruitment Status: Not yet recruiting
• First Posted: April 17, 2024
• Last Update Posted: April 17, 2024
• Sponsor: IRCCS Eugenio Medea
• Collaborators: IRCCS National Neurological Institute "C. Mondino" Foundation; Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Information provided by (Responsible Party): IRCCS Eugenio Medea

Tracking Information

• First Submitted Date: April 2, 2024
• First Posted Date: April 17, 2024
• Last Update Posted Date: April 17, 2024
• Estimated Study Start Date: April 15, 2024
• Estimated Primary Completion Date: March 14, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2024)

• Assisting Hand Assessment (AHA) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  This scale enables to quantify the assistance provided by the more affected hand to the less affected hand during bimanual activities. This observation-based, criterion-referenced assessment highlights a person's typical performance, emphasizing practical functionality over maximal capacity, and serves as a reliable measure of change over time. The scale comprised 20 items, scored on a 4-point Likert scale, from 1 to 4. The total score indicates how well the more affected hand is used as an assisting hand. A score of 20 means poor performance (the hand is not used as an assisting hand); a score of 80 means that the hand is used effectively. The results are converted for each of the three scales to logits by a Rasch analysis, on a 0-to-100 scale (with higher scores suggesting better use).
• Box and Block Test (BBT) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  This test is designed to measure manual dexterity. It is quick, simple, and cost- effective. It involves a box with a partition in the middle placed on a table, with a total of 150 blocks on one side of the partition. The score of the test is given by the number of blocks transported within a minute. Higher values suggest better performance. The BBT provides a reliable and objective measurement of manual dexterity, making it valuable for evaluating functional outcomes and monitoring progress in rehabilitation programs over a short period of time.
• Visuomotor task [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  The visuomotor task is an ad hoc computer based task. It involves a mouse click- and-drag operation where an object appears at the center of the screen. The objective is to drag and drop the object to the location indicated by a previously presented arrow, pointing towards a target object within a configuration of objects. Participants are required to focus on the arrow's direction, swiftly and accurately moving the central object to its designated target location. This task enables the measurement of movement time (in milliseconds; consisting in the time necessary to move the object in the target position); precision error (calculated as the distance, in pixels, between the drop position of the object and the actual target position); the proportion of overtime errors (the percentage of trials in which responses are too slow). Smaller values of Movement time, Precision error and overtime errors will suggest better performance.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: April 16, 2024)

• Canadian Occupational Performance Measure (COPM) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  This is a client-centered, semi-structured interview used in occupational therapy to identify the problems experienced by the patients. This interview engages the patient in recognizing daily occupations of importance that he/she want to do, need to do, or are expected to do but is unable to accomplish. Upon the identification of the problems experienced in patient's everyday-life activities the patient is asked to rate the importance of each activity in his/her life though a 10-points rating scale and then, to select up to five problems to be addressed during the intervention. Lastly, the patient is asked to rate on a 10 points scale his/her own level of performance and satisfaction in performing that activity for each of the five problems (from 0, low performance or low satisfaction to 10, high performance or high satisfaction).
• Children's Hand-Use Experience Questionnaire (CHEQ) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  The questionnaire includes 27 bimanual activities. Each activity is rated on three scales measuring: i) the perceived efficacy of the activity ("How do you think the child's hand works?") from 1 (Bad / not used hand) to 4 (Good efficacy); ii) the amount of assistance and the time needed to perform the activity ("How much time does your child need to do the whole task, compared to peers?) from 1 (Considerably longer) to 4 (Equally long time compared to other peers); and iii) the child's satisfaction with their performance ("Is your child bothered by his/her reduced hand/arm function during this activity?") from 1 ("It bothers him/her a lot") to 4 ( "It does not bother him/her at all"). The questionnaire provides a result corresponding to the summary of the ratings. The results are converted for each of the three scales to logits by a Rasch analysis, on a 0-to-100 scale (with higher scores suggesting better performance/satisfaction).
• Melbourne Assessment 2 (MA2) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  This scale allows evaluating the unimanual performance of both the more and less affected hand. It measures four elements of upper limb movement quality: movement range, accuracy, dexterity and fluency. It consists of 14 test items that require children to interact (by reaching, grasping, releasing and manipulating) with simple objects. Movement elements are scored on a 3-, 4-, or -5 point scale according to specific criteria. Scores are arranged into the 4 sub-scales (movement range, accuracy, dexterity and fluency) according to the element of movement being rated. A child's total raw score for each sub-scale is converted to a percentage of the maximum possible score for that sub-scale, with higher scores indicating better performance.
• Gross Motor Function Measure (GMFM-66) [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  It is a standardized observational tool used by healthcare professionals to evaluate and quantify the gross motor abilities and limitations of children with CP. It assesses 66 motor skills across five dimensions: lying and rolling, sitting, crawling and kneeling, standing, and walking, running, and jumping. Each skill is scored on a 4-point scale, ranging from 0 (does not initiate) to 3 (performs fully).
• Vineland Adaptive Behavior Scale Version 2 (VABS II) [ Time Frame: 1-2 days before the start of training (t0), three months after the end of the training (t2) ]
  This is a tool designed to assess adaptive behavior in individuals from birth to age 90. It assesses 11 subdomains of adaptive behavior grouped into four domains; sums of these scores are standardized into Communication, Daily Living Skills, Socialization and Motor Skills domain standard scores. Sums of the domain standard scores are then standardized into the Adaptive Behavior Composite score ranging from 20 to 160 (mean=100; standard deviation= 15).
• Pediatric quality of life inventory PedsQL(cerebral palsy module), (PEDS-QL) [ Time Frame: 1-2 days before the start of training (t0), three months after the end of the training (t2) ]
  This is a widely employed, brief, and standardized self-reporting tool for assessing health-related quality of life in children and young individuals. The measure can be completed by parents (the Proxy Report) as well as children and young people (the Self-Report) with versions available for children and young people aged 5-7, 8-12, and 13-18. Parent-rated versions are available for children aged 2-4, 5-7, 8-12, and 13-18. The versions from 5 to 18 years comprise 35 items comprising 7 dimensions: Daily Activities; School Activities; Movement and Balance; Pain and Hurt; Fatigue; Eating Activities; Speech and Communication. For each item, consisting in everyday life action, it is required to indicate how much of a problem each item has been in the past month with response options from 0 (never a problem) to 4 (almost always a problem). The items are reverse scored and transformed to a 0-100 scale, with higher scores indicating better health related quality of life.
• Cortical rhythms at rest and during the Visuomotor task [ Time Frame: 1-2 days before the start of training (t0), 1-2 days after the end of the training (t1), three months after the end of the training (t2) ]
  Cortical rhythms will be recorded using EEG electrodes placed over the fronto-central regions to investigate potential changes in EEG power in gamma (30- 100 Hz) bands. We will investigate the event-related synchronization/desynchronization (ERS/ERD) of this frequency, reflecting an increase or decrease in power within the EEG signal during the visuomotor task compared to the resting state condition. This analysis will focus on regions associated with cognitive and motor control, aiming to detect any changes indicative of treatment effects.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 16, 2024)

• Heart rate (HR) [ Time Frame: in the first 2 minutes and after 20 minutes of stimulation session ]
  To assess the safety of the stimulation, the HR (beats per minute, bpm) will be checked. HR values will be check during a two minutes rest condition. For this measure, more caution will be held with values lower than 70 or higher than 120 bpm in 6 to 12 years old children and lower than 60 or higher than 100 bpm in 12 to 18 years old adolescents.
• Oxygen saturation (SPO2) [ Time Frame: in the first 2 minutes and after 20 minutes of stimulation session ]
  To assess the safety of the stimulation, the SPO2 (%) will be checked, too. SPO2 values will be check during a two minutes rest condition. Cases with SPO2 values lower than 93% will be carefully checked.
• Tolerability of the stimulation [ Time Frame: immediately after every stimulation sessions of the 10-days training ]
  Tolerability will be assessed through a 10 centimetres Visual Analogue Scale by asking to indicate the level of discomfort during the stimulation, and to rate on Child-friendly Likert scales the intensity of the following sensations: itching, pain, burning, heat, pinching, iron taste, fatigue, visual sensations like flashes, eyelid movements, others. For each sensation the patients will be asked to express a value of perception strength that ranges from 0 (absence) to 4 (strong). Higher values will suggest stronger discomfort.
• number of patients who accept to complete the 2-week training [ Time Frame: 1-2 days after the end of the training (t1) ]
  This value will be expressed as percentage, with respect to the total number of recruited patients. Higher values will suggest higher feasibility of the training
• number of sessions completed per patient [ Time Frame: 1-2 days after the end of the training (t1) ]
  This value will be expressed as mean percentage of session completed (across patients), with respect to the total number of session planned for the training. Higher values will suggest higher feasibility of the training
• acceptability of the training [ Time Frame: 1-2 days after the end of the training (t1) ]
  The acceptability will be assessed by asking to the child/adolescent and his/her parents subjective evaluation of training accessibility and efficacy. Questions like "I find it difficult to motivate my child for doing the training"/ "I find it difficult to start the training"; or "I would suggest this training to other people I know"/ "I think other people I know would enjoy doing this training" will be rated from 1 (completely disagree) to 5 (completely agree). Response will be reversed in the negative items, so that higher scores will suggest more positive evaluation/higher acceptability.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Transcranial Alternating Current Stimulation in Cerebral Palsy (BOOSTTACS)
• Official Title: tACS-combined Motor Training for the Rehabilitation of the Upper Limb in Children and Young People With Cerebral Palsy: a Randomized, Sham-controlled Trial
• Brief Summary: The present study aims to assess, through a randomized controlled trial (RCT), the efficacy of transcranial alternating current stimulation (tACS) in enhancing the functional changes due to an intensive motor training in children and adolescents with Cerebral Palsy (CP). Particularly, in two different groups active or sham tACS will be paired with the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) and we will assess the effects on the upper limbs motor ability and daily functioning in 6 to 17 years old patients with CP having mild-to moderate upper limb deficits. The investigators hypothesized that, thanks to the intensive bimanual training, both the active and the sham group will improve in motor functioning. However, in light of findings showing that tACS effectively improves motor learning, the investigators hypothesized that active tACS might improve in a greater and more lasting extent than sham tACS the motor functioning. Moreover, as suggested by previous studies investigating the effect of non-invasive brain stimulation (NIBS) in pediatric population, the investigators expected that the treatment will be safe and well tolerated. Such a result would encourage the use of NIBS to boost the rehabilitative training of motor abilities in children and adolescents with CP.

Detailed Description

This represents one of the two RCTs of the project "Bottom-up and tOp-down neuromOdulation of motor plaSTicity in cerebral palsy" (BOOST; FRRB 3438840).The study will be a randomized, sham controlled, pre-test/post-test study involving 44 children and adolescents with CP. Patients will be treated in pairs, with a matching of motor deficit severity, IQ, or age. Each pair will be randomly assigned to the active or to the sham tACS group, stratifying the pairs between the two groups based on motor deficit severity, IQ, or age. Both groups will undergo a bimanual training in an ecological and highly motivating environment during the application of the tACS. During the training, starting from a set of proposals the choice of the type of activities to be practiced in each session will be left to patients, boosting the motivational aspect of the training. This will also ensure an individualized and goal directed approach. The therapists will monitor and modify the activities within each pair to ensure that the intervention maintains the quality of the individualized intervention. The positions performed during bimanual tasks and the activities of daily living will be designed to systematically engage postural control of the trunk and lower limbs according to Habit-ILE protocol. The rehabilitation treatment will be carried out for 5 consecutive days for 3h/day for 2 weeks (30 hours of intervention overall). Children and adolescents will be assessed before the start of treatment (T0), immediately after the end of intensive treatment (T1) and three months after the end (T2). The overall RCT will be structured as follows. In the first session prior the beginning of the training (t0), the RCT will include the administration of all clinical assessment measures and the patients will be asked to perform for 10 minutes an ad-hoc computer based Visuomotor task (please refer to the outcome sessions for more detailed description). Cortical rhythms will be recorded by electroencephalogram (EEG) both before (during rest) and during the execution of the Visuomotor task. Analysis of the resting-state EEG will be conducted to derive the Individualized Gamma Frequency (IGF), which will be matched to each patient's specific stimulation frequency delivered through tACS during the training. Patients will undergo the 10 days treatment. For each training day, the treatment will last three hours. During the first 20 minutes of treatment the active or sham tACS (according to the group allocation) will be delivered. Before starting and 20 minutes after the end of the stimulation the vital parameters will be checked. After the end of the stimulation, patients will be also asked to rate the sensations experienced during the stimulation through Visual Analogue Scales and through child-friendly Likert scales. Then, they will continue the training for the remaining session time without stimulation. Soon after the end of all the training sessions, patients will carry the t1 evaluation. As for the t0 session, this session will include the administration of the clinical assessment measures and execution for 10 minutes of the Visuomotor task. Three months after the end of the training (t2) the follow up assessment will be conducted, following the same exact procedure of t0.

Primary outcomes will include the following clinical measures: the Assisting Hand Assessment (AHA), the Box and Block Test (BBT) and the performance at the Visuomotor task. Secondary outcome will include the scores at the following tests: the Children's Hand Experience Questionnaire (CHEQ), the Canadian Occupational Performance Measure (COPM), the Gross Motor Function Measure (GMFM-66), the Melbourne Assessment-2 (MA2) scale, the Vineland Adaptive Behavior Scale Version 2 (VABS 2), the Pediatric Quality of Life Inventory (PEDS-QL), and the cortical rhythms registered via EEG at rest and during the Visuomotor task. Vital parameters (the oxygen saturation (SPO2) and the Heart Rate (HR)), and the scores at the questionnaires assessing stimulation- induced sensations will be also checked to assess the safety and the tolerability of the stimulation. Lastly, the feasibility and the acceptability of the training will be assessed by considering, respectively, the number of patients completing the training/the number of sessions for each patient and the response to ad hoc questionnaires for the patients and their guardians.

All primary and secondary outcomes will be collected at each time point, except for the PedsQL and VABS-II, that will be administered only at T0 and T2. Furthermore, vital parameters and the questionnaires assessing stimulation-induced sensations will be examined during each stimulation session. The acceptability questionnaires will be administered only after the end of the training (t1).

The patients and their guardians, the personnel responsible for conducting the bimanual training and analysing clinical data will be kept blind to the group allocation. Instead, the coordinator of the study, the staff who will apply the tACS will be "not blind". With respect to the clinical assessment, whenever possible the staff administering and scoring the scales will be blinded to group allocation. Questionnaire scores and neuropsychological tests will not contain personal information about the subjects, who will be identified by an alphanumeric code. All records that contain names or other personal identifiers, such as informed consent forms, will be stored separately from study records identified by code number. In order to uphold the overall quality of the clinical trial, instances of code breaks should be limited to exceptional circumstances, where knowledge of the actual treatment is deemed absolutely necessary for the ongoing management of the patient.

The intensive treatment will take place at IRCCS E. Medea "Associazione La Nostra Famiglia" in Bosisio Parini (Lecco), at Fondazione Mondino IRCCS (Pavia) and at ASST Ospedali Civili di Brescia.

This trial is supported by Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia), project FRRB 3438840 BOOST "Bottom-up and tOp-down neuromOdulation of motor plaSTicity in cerebral palsy".

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cerebral Palsy

Intervention

Device: transcranial Alternating Current Stimulation

tACS will be performed by using a Conformite Europeenne (CE) marked stimulator device (Starstim ®, Neuroelectrics, Barcelona, Spain). By applying alternating current at the gamma frequency band (range 30-80), known to be associated to motor performance, tACS can entrain or synchronize neural oscillations in the targeted brain regions. By modulating cortical excitability of the cerebellum, a region strongly involved in motor learning and coordination, tACS is expected to influence the strength and coordination of motor responses elicited during the training. tACS will be delivered through two saline-soaked surface sponge electrodes (dimension: 25cm2 each), one placed over F3 (left frontal region) and the other over the right cerebellar hemisphere. The intensity will be set to 1mA, and this value will be gradually reached with a ramping-up phase of 30 secs. The frequency of the stimulation will match the IGF identified during the EEG recording performed at rest.

Study Arms

• Experimental: Active tACS combined with the training
  The tACS will be applied for the first 20 minutes of the training, every day of the treatment. Before and the after of the stimulation, SpO2 and HR will be checked. After the stimulation participants will be asked to rate the sensations and possible side effects occurring during tACS. The intensive bimanual training will be administered by following the procedure described in the Detailed Description session, as for the Sham tACS combined with the training arm.
  Intervention: Device: transcranial Alternating Current Stimulation
• Sham Comparator: Sham tACS combined with the training
  The sham-tACS will be applied for the first 20 minutes of the training, every day of the treatment. However, in this condition, after the initial 30 seconds of ramp-up phase of the current, the stimulation will be 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 enhanced the plausibility of the sham condition.Before and the after of the stimulation, SpO2 and HR will be checked. 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 feeling on several visual analogue scales and Likert scales. The intensive bimanual training will be administered by following the procedure described in the Detailed Description session, as for the Sham tACS combined with the training arm.
  Intervention: Device: transcranial Alternating Current Stimulation

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 16, 2024): 44
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 14, 2026
• Estimated Primary Completion Date: March 14, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• clinical signs of unilateral or bilateral upper limb deficits (with a difference at least of 25% between more affected and less affected hand at Box and Block test);
• Magnetic Resonance Imaging (MRI) confirmed diagnosis according to Surveillance of Cerebral Palsy (SCPE) criteria;
• Manual Ability Classification System (MACS) level I,II,III;
• Gross Motor Function Classification System (GMFCS) level I,II,III;
• Visual Function Classification System (VFCS) I-II-III;
• Intelligence quotient (IQ) > 50.

Exclusion Criteria:

• presence of cochlear implant, cardiac pacemaker, ventriculoperitoneal shunt, neuro-stimulators, clips, fragments or metal splinters in the brain or skull except for titanium;
• treatments for spasticity or functional surgery of the upper limb in the previous 6 months or planned during the duration of the study;
• uncontrolled epileptic seizure in the last 2 years.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT06372041
• Other Study ID Numbers: 944/B
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized dataset will be available at https://osf.io/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: Before data analyses, for ten years.
• Access Criteria: all
• URL: https://osf.io/

• Current Responsible Party: IRCCS Eugenio Medea
• Original Responsible Party: Same as current
• Current Study Sponsor: IRCCS Eugenio Medea
• Original Study Sponsor: Same as current

Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation
• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

• Investigators: Not Provided
• PRS Account: IRCCS Eugenio Medea
• Verification Date: April 2024