Impact of rTMS Combined With Neurorehabilitation on Lower Extremity Motor Function and Spasticity in Children With Spastic Diplegic Cerebral Palsy

1\. Aim and Significance of the Research Cerebral palsy (CP) is the most common cause of lifelong physical disability observed in childhood in most countries, with a prevalence ranging from 1.5 to 2.5 per 1,000 live births; in our country, this rate is 4.4.

CP is a group of permanent disorders affecting the development of movement and posture, leading to activity limitation, attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. Motor disorders in CP are frequently accompanied by sensory and perceptual problems, cognitive impairments, communication and behavioral issues, epilepsy, and secondary musculoskeletal problems.

Diplegic CP is the most common subtype of spastic CP, with prematurity identified as the primary etiology. In children with spastic diplegia, all four extremities are involved; however, the lower extremities are significantly more affected than the upper extremities. A loss of fine motor skills is frequently observed in the upper extremities.

Most children with spastic diplegia may become significantly disabled due to these symptoms, which profoundly impacts the lives of both the child and the entire family. This situation underscores the importance of comprehensive CP rehabilitation. The rehabilitation program should be initiated as early as possible, considering the child's age and functional status, and must continue throughout their lifetime. When planning CP rehabilitation, an individualized program should be developed based on the child's specific needs. Our primary goal in CP rehabilitation should be to ensure that children participate in social life with the minimum possible level of disability.

In CP rehabilitation, therapeutic modalities such as neurophysiological exercises, conventional exercises, gait training, orthotics, the use of assistive devices, spasticity management, occupational therapy, cognitive rehabilitation, speech and swallowing therapy, hydrotherapy, robotic treatments (virtual reality applications, balance devices, etc.), Functional Electrical Stimulation (FES) applications (e.g., FES cycling), and visual rehabilitation are prescribed according to the patient's condition and needs. Alongside these modalities, research in pediatric neurology has focused on the efficacy of Non-Invasive Brain Stimulation (NIBS) for treating various pediatric neurological disorders. For any therapeutic modality to demonstrate an effective and long-lasting therapeutic impact, it must possess a function that influences the brain's neuroplasticity in the long term. Theoretically, a treatment method that acts directly on the cerebral cortex or neurons may support the development of the nervous system and correct dysfunction more effectively than the traditional bottom-up regulation and remodeling of the central nervous system through peripheral organ stimulation.

One of the novel diagnostic and therapeutic options in CP is Transcranial Magnetic Stimulation (TMS), a type of NIBS that has been shown to be effective in improving outcomes for children with CP. The objective of TMS is to stimulate neurons in targeted regions and their associated neuronal networks through an intact skull using a coil. This stimulation modulates the neuronal activity pattern in the targeted cortical area: it achieves this by providing an inhibitory effect when used at low frequencies (1-5 Hz) or an excitatory effect when used at high frequencies (5-20 Hz), thereby restoring neuronal balance in the brain.

Studies indicate that rTMS can improve motor function, reduce spasticity, enhance balance control, and improve speech function in patients with CP.

Although the limited number of studies on TMS in CP creates some hesitation regarding safety, a significant conclusion drawn from clinical trials conducted with rTMS to date is that this method is safe and well-tolerated in children with CP. No serious adverse events have been reported in any studies within the field of pediatric rTMS. However, transient headaches, neck pain, scalp tenderness, redness, and tingling or twitching of the facial muscles may occur in rare cases during application. Seizure induction has been reported as an extremely rare occurrence.

While the use of rTMS in the treatment of children with CP is becoming increasingly common today, most studies have focused on its effects on upper extremity function. Only one study specifically included children with bilateral CP; however, that study investigated the impact of rTMS on the disruption of the structural brain network using functional MRI (fMRI) and did not report any effects on clinical symptoms.

This study aims to investigate the short- and long-term effects of rTMS on lower extremity motor function and spasticity in children with spastic diplegic cerebral palsy. This will be achieved by comparing children receiving rTMS combined with a neurological rehabilitation program with those receiving the neurological rehabilitation program alone.

New studies are required in the literature to standardize the methodology for prescribing rTMS. This study is expected to contribute to future research on the development and optimization of rTMS protocols for children with spastic diplegic cerebral palsy.

Studies demonstrate that rTMS can improve motor function, reduce spasticity, enhance balance control, and improve speech function in patients with CP.

3\. Expected Benefits and Risks of the Research rTMS is a painless, non-invasive, and safe modality of brain stimulation. Although the limited number of studies on TMS in CP may create some hesitation regarding safety, a significant conclusion from clinical trials conducted to date is that this method is safe and well-tolerated in children with CP. No serious adverse events have been reported in rTMS studies; however, transient headaches, neck pain, scalp tenderness, redness, and tingling or twitching of the facial muscles may occur in rare cases during application. Seizure induction has been reported as an extremely rare occurrence.

Furthermore, literature suggests that 'TMS applications should be encouraged for inclusion in practical applications within the field of pediatric neurology. There are no specific risks associated with this method, other than the general contraindications applicable to all electrical and magnetic stimulation techniques.

This study is designed as a randomized controlled, prospective, and observational study. Children with spastic diplegic CP who are receiving inpatient treatment at the Pediatric Rehabilitation Clinics of Ankara Bilkent City Hospital, Physical Medicine and Rehabilitation Hospital, and who meet the inclusion and exclusion criteria will be enrolled. Informed consent forms will be obtained from the patients (or their legal guardians) indicating their voluntary participation.

Power analysis was performed using G\*Power 3.1 software. Based on an effect size of 0.70 (large effect), an alpha level (a) of 0.05, and a power (1-beta) of 0.90, with a moderate correlation (0.50) between measurements, the minimum sample size required to detect a statistically significant difference both between groups and between measurements was calculated as 18 (9 patients per group). To ensure robustness, a total of 20 patients will be included, with 10 patients in each group. Patients will be randomly assigned to two groups of 10 based on their order of enrollment. One group will receive the neurological rehabilitation program alone, while the other group will receive the neurological rehabilitation program combined with rTMS.

The neurological rehabilitation program consists of 45 minutes of daily weekday sessions with a physiotherapist (including range of motion, stretching, strengthening, and neurophysiological exercises), occupational therapy (30 minutes, twice a week), child development and education sessions (20 minutes, three times a week), and a total of 10 sessions of lower extremity robotic rehabilitation (20 minutes, twice a week). These treatments will be administered to all children. In the study group, rTMS will be applied in addition to this neurological rehabilitation program, with the rehabilitation sessions following the rTMS application.

Magnetic stimulation will be performed using a Magstim Rapid2 Magnetic Stimulator (Magstim, Whitland, Dyfed, UK). The protocol includes 20 total sessions (5 times per week for 4 weeks), with each session lasting 20 minutes at a frequency of 5 Hz. Stimulation will be delivered using a 70 mm outer diameter figure-of-eight coil positioned at the midline of the cranial apex while the children are in a seated position, providing a total of 1000 pulses per session. Patients included in the study will be evaluated at baseline (pre-treatment), immediately after the intervention (post-treatment), and at a 12-week follow-up from the start of treatment.

5\. Number of Patients and Volunteers, Their Characteristics, and Rationale for Selection (Age Range, Gender, etc.) The study is planned to include 20 children (both male and female) with Spastic Diplegic Cerebral Palsy, aged between 5 and 18 years. Participants must be cooperative and oriented, with a Gross Motor Function Classification System (GMFCS) level of II or III.

Demographic data such as Participant ID , age, gender, height, weight, and educational level, as well as clinical history including medications, comorbidities, affected side, rehabilitation history, and prenatal, natal, and postnatal history, will be recorded for patients in both study groups.

Gross Motor Function Classification System (GMFCS):

This is a widely used classification system in CP-related research. It is a valid and reliable scale for classifying the severity of gross motor function limitations in children with CP. It defines the major functional characteristics of children with CP by dividing them into four age groups: under 2 years, 2-4 years, 4-6 years, and 6-12 years. Children at Level I are the most independent in motor functions, while children at Level V are the most dependent.

Bimanual Fine Motor Function (BFMF) Scale: The Surveillance of Cerebral Palsy in Europe Network (SCPE-NET) has proposed classifying spastic CP as unilateral or bilateral and combining these definitions with GMFCS levels for the lower extremities and BFMF levels for the upper extremities. BFMF is a new classification method developed for the upper extremities, consistent with the five levels found in the GMFCS.

Modified Ashworth Scale (MAS): The Modified Ashworth Scale (MAS) is used to assess the severity of spasticity. The joint is moved passively through its range of motion, and the perceived resistance is evaluated. (MAS 0: No increase in muscle tone; 1: Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion; 1+: Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout less than half of the remainder of the range of motion; 2: More marked increase in muscle tone through most of the range of motion, but affected part(s) easily moved; 3: Considerable increase in muscle tone, passive movement difficult; 4: Affected part(s) rigid in flexion or extension).

Functional Mobility Scale (FMS): The FMS is an assessment system designed to measure changes in walking ability that can be observed following interventions. The FMS classifies children's performance across three distances (5, 50, and 500 meters) based on their need for a wheelchair or assistive devices. Unlike the GMFCS, significant changes in FMS levels are observed following orthopedic surgery or other clinical interventions.

Gross Motor Function Measure-88 (GMFM-88): The GMFM-88 is an assessment method used to determine the motor development level of children with Cerebral Palsy, and its validity and reliability have been well-established. The purpose of the GMFM is to measure "how much of a movement" a child can complete rath

• Timed Up and Go (TUG) Test [Срок оценки: Patients included in the study will be evaluated at baseline (pre-treatment), immediately after the intervention (post-treatment), and at a 12-week follow-up from the start of treatment.]
• Functional Mobility Scale (FMS) [Срок оценки: Patients included in the study will be evaluated at baseline (pre-treatment), immediately after the intervention (post-treatment), and at a 12-week follow-up from the start of treatment.]