Impact of rTMS Combined With Neurorehabilitation on Lower Extremity Motor Function and Spasticity in Children With Spastic Diplegic Cerebral Palsy
Impact of rTMS Combined With Neurorehabilitation on Lower Extremity Motor Function and Spasticity in Children With Spastic Diplegic Cerebral Palsy
Cerebral palsy (CP) is widely recognized as the most prevalent cause of lifelong physical disability emerging in childhood across most global populations. While international data typically reports a prevalence ranging from 1.5 to 2.5 per 1,000 live births, in our specific national context, this rate is notably higher, reaching 4.4 per 1,000. CP is defined as a heterogeneous group of permanent disorders that fundamentally disrupt the development of movement and posture. These disruptions lead to significant activity limitations and are attributed to non-progressive disturbances occurring in the developing fetal or infant brain. Beyond primary motor impairments, CP is frequently characterized by a complex constellation of associated symptoms, including sensory and perceptual deficits, cognitive impairments, communication difficulties, behavioral challenges, epilepsy, and secondary musculoskeletal complications that develop over time.Among the various clinical presentations, diplegic CP stands out as the most common subtype of spastic CP, with prematurity identified as the leading etiological factor. In children diagnosed with spastic diplegia, all four extremities are typically involved; however, the clinical hallmark of this subtype is that the lower extremities are significantly more affected than the upper extremities. Despite this lower-body dominance, a loss of fine motor skills is frequently observed in the upper extremities as well. Most children with spastic diplegia face the risk of becoming significantly disabled due to these combined symptoms, a situation that exerts a profound and lasting impact on the quality of life for both the child and their entire family.This complex clinical picture underscores the critical importance of implementing a comprehensive and multidisciplinary CP rehabilitation program. Such programs must be initiated as early as possible, tailored to the child's specific age and functional status, and maintained throughout their entire lifespan. The planning of CP rehabilitation requires a highly individualized approach based on the unique needs of each patient. The ultimate and primary goal of these interventions is to facilitate the child's full participation in social life while maintaining the minimum possible level of physical and functional disability.In contemporary CP rehabilitation, a wide array of therapeutic modalities is employed. These include neurophysiological exercises, conventional physical therapy, gait training, orthotics, assistive devices, and pharmacological spasticity management. Furthermore, occupational therapy, cognitive rehabilitation, speech and swallowing therapy, hydrotherapy, and advanced robotic treatments-such as virtual reality applications and balance-training devices-are integrated into the patient's care plan. Functional Electrical Stimulation (FES), including specialized applications like FES cycling, and visual rehabilitation are also prescribed according to individual requirements.In addition to these traditional methods, recent research in pediatric neurology has increasingly focused on the efficacy of Non-Invasive Brain Stimulation (NIBS) for various pediatric neurological disorders. For any therapeutic modality to demonstrate a truly effective and long-lasting impact, it must influence the brain's neuroplasticity over the long term. Theoretically, treatment methods that act directly on the cerebral cortex or specific neuronal populations may support nervous system development and correct dysfunction more effectively than traditional "bottom-up" approaches. While traditional methods rely on remodeling the central nervous system through peripheral organ stimulation, NIBS offers a "top-down" regulatory mechanism.One of the most promising novel diagnostic and therapeutic options in CP management is Transcranial Magnetic Stimulation (TMS), a specific form of NIBS that has shown effectiveness in improving clinical outcomes for children. The fundamental objective of TMS is to stimulate neurons in targeted cortical regions and their associated networks through an intact skull using a magnetic coil. This technology modulates neuronal activity patterns: it achieves an inhibitory effect when applied at low frequencies (1-5 Hz) or an excitatory effect at high frequencies (5-20 Hz), thereby aiming to restore a healthy neuronal balance in the brain.Extensive clinical studies indicate that repetitive TMS (rTMS) can significantly improve motor function, reduce spasticity, enhance balance control, and even improve speech functions in CP patients. Although the relatively limited number of pediatric studies sometimes leads to hesitation regarding safety, current clinical evidence suggests that rTMS is a safe and well-tolerated intervention for children with CP. No serious adverse events have been reported in pediatric rTMS trials to date. Rare side effects, when they occur, are typically transient and mild, including minor headaches, neck pain, scalp
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 rather than the quality of the motor performance. The test consists of five subsections: Lying and Rolling (A), Sitting (B), Crawling and Kneeling (C), Standing (D), and Walking, Running, and Jumping (E). It comprises a total of 88 items: 17 in the lying and rolling section, 20 in the sitting section, 14 in the crawling and kneeling section, 13 in the standing section, and 24 in the walking, running, and climbing stairs section.
Gross motor functions are evaluated based on the degree of achievement for each item. Scoring is performed using a Likert scale: 0 if the child cannot initiate the activity, 1 if they initiate it independently, 2 if they partially complete it, and 3 if they complete it independently. The maximum total score is 264. While a total score can be calculated, it is also possible to calculate scores for each section individually. The child's score for each section is calculated as a percentage; the percentages of all sections are then averaged (divided by 5) to obtain the total GMFM-88 score.
Since ambulatory patients will be enrolled, scores for Sections D and E will be specifically calculated.
Timed Up and Go (TUG) Test: "The Timed Up and Go (TUG) test is a practical and reliable tool used to assess functional mobility, dynamic balance, and transfer skills in children. It is a sensitive measure for monitoring changes in gross motor function, particularly in children with CP.
The test begins with the child seated in a back-supported chair. Upon command, the child stands up, walks a marked 3-meter distance, turns around, returns, and sits back down in the chair. The time taken to complete this activity is recorded in seconds. The use of daily assistive devices (e.g., walkers, crutches) is permitted during the test but must be documented.
6. Location of Assessments and the Evaluating Personnel The assessment of patients' demographic data, Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure (GMFM), Timed Up and Go (TUG) Test, Functional Mobility Scale (FMS), Bimanual Fine Motor Function (BFMF) Scale, and Modified Ashworth Scale (MAS) will be performed by Dr. Özlem KAYNAR ŞİŞMAN, under the supervision of Prof. Dr. Canan Çulha, at the Ankara Bilkent City Hospital, Physical Medicine and Rehabilitation Hospital.
7. Differentiation Between Routine Parameters and Research-Specific Parameters "Recording of demographic data (participant ID, age, gender, height, weight, and educational level), medical history (medications, comorbidities, affected side, rehabilitation history, prior upper extremity treatments, prenatal, natal, and postnatal history), and family history is part of the routine clinical assessment. Furthermore, the determination of GMFCS levels, BFMF levels, and the assessment of spasticity using the Modified Ashworth Scale are performed routinely. Conversely, the Timed Up and Go (TUG) Test and the Gross Motor Function Measure (GMFM) will be conducted specifically for the purposes of this research.
8. Anticipated Study Duration, Start and End Dates The study will commence immediately following the receipt of approval from the Ethics Committee." 9. Inclusion, Exclusion, and Withdrawal Criteria
Inclusion Criteria:
Between 5 and 18 years of age.
Cooperative and oriented (capable of following commands).
Gross Motor Function Classification System (GMFCS) Level II or III.
Diagnosis of Spastic Diplegic Cerebral Palsy.
Exclusion Criteria:
Poor general health status.
Children with severe comorbid conditions (e.g., total or partial blindness, severe lower extremity deformities, etc.).
Diagnosis of epilepsy.
History of seizures.
Presence of a cardiac pacemaker.
Presence of metal implants (specifically in the cranial and cervical regions).
Open wounds or infections at the application site.
History of botulinum toxin injection or surgical intervention within the 6 months prior to study enrollment.
History of Selective Posterior Rhizotomy (SPR) surgery. Participants may withdraw from the study at any time upon request, or if serious adverse events occur, or due to non-compliance with the study protocol.
10. Study Termination Criteria
Occurrence of any unexpected adverse effects during the rTMS application.
Development of seizures following the rTMS application. 11. Statistical Methods for Data Evaluation Statistical analysis will be performed using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). The normality of the data distribution will be assessed using the Shapiro-Wilk test. In descriptive analyses, continuous variables with normal distribution will be expressed as mean pm standard deviation, while non-normally distributed continuous variables will be presented as median and interquartile range (IQR). Categorical variables will be expressed as the number of cases (n) and percentages (%).
To compare quantitative variables between groups, the Independent Samples T-test will be used for normally distributed data, and the Mann-Whitney U test will be used for non-normally distributed data. Categorical variables will be compared using the Chi-Square test or Fisher's Exact test. The Friedman test will be applied to evaluate intra-group changes across pre-treatment and follow-up assessments. A p-value of < 0.05 will be considered statistically significant. When significant results are obtained, post-hoc pairwise comparisons will be performed using the Wilcoxon Signed-Rank test with Bonferroni correction.
Inclusion Criteria:
Exclusion Criteria:
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