Children with spastic cerebral palsy (SCP) have limb spasticity, movement disorders, and abnormal posture due to injury to the cerebral cortex motor area, resulting in inability to stand and walk normally. Therefore, alleviating limb spasticity and enhancing gross motor function in children with SCP have become important therapeutic goals.
This study presents the results of a randomized controlled trial utilizing a 2 x 2 factorial design, comparing the effects of repeated transcranial magnetic stimulation (rTMS) and action observation training (AOT) intervention methods on spasticity, balance function, and motor function in children with spastic cerebral palsy (SCP). The study aimed to investigate whether the combination of the two interventions produces greater improvement than either treatment alone or conventional treatment.
Subject children in this study, in accordance with the random number table, were randomly divided into four groups: conventional group, rTMS group, AOT group, and combined intervention group. All the children in the four groups received conventional rehabilitation treatment, on the basis of which they were given different therapeutic programs of rehabilitation measures. The conventional group had no other treatment while the rTMS group received rTMS, the AOT group received AOT and the combined intervention group was given a combined intervention of rTMS and AOT. They were trained five days per week for 12 weeks. Changes in scores of spasticity, balance function, walking ability, and gross motor function were assessed at the onset of the training program and upon completion of 12 weeks of treatment.
A total of 64 Children with SCP completed the study, and their results were analyzed. The total gross motor function efficiency of 87.50% in the experimental group was significantly higher than that of 25.00% in the conventional group, 62.50% in the rTMS group, and 68.75% in the AOT group. The preliminary results showed that combined intervention of rTMS and AOT could effectively improve the balance function and motor function of children, and the therapeutic effect of the combined intervention was better than that of conventional treatment, rTMS or AOT alone. Finally, clinical efficacy and optimal treatment parameters of the combined intervention were clarified to provide a clinical basis for therapists to conduct lower limb function rehabilitation for children with SCP.
Cerebral palsy1 (CP) is one of the most common disabling disorders in children and is a group of persistent syndromes caused by non-progressive brain damage in developing fetuses and infants, including central dyskinesia, abnormal posture, and limited mobility. Currently, there are approximately 17 million children worldwide affected by cerebral palsy2, with over 5 million cases in China. Among various forms of cerebral palsy, spastic cerebral palsy (SCP) accounts for roughly 80%3. Children with SCP suffer from brain damage resulting in muscle spasms, diminished sensory function, impaired muscle coordination, and decreased balance capabilities, all of which hinder independent walking and daily activities. Current rehabilitation measures for enhancing gross motor function in children with SCP encompass activities such as core stability training4, task-oriented training5, constraint-induced movement therapy6, and mirror visual feedback therapy7. These measures can improve clinical symptoms of children by regulating and reshaping the central nervous system from bottom to top by improving the functions of peripheral organs.
Transcranial magnetic stimulation (TMS)8,9 is a painless, non-invasive, and safe therapeutic method. rTMS refers to the continuous release of stimuli at equal intervals after a single command, which is one of the regular repetitive stimulation patterns. Based on the principle of electromagnetic induction and electromagnetic conversion, it applies transient currents through stimulation coils to form a pulsed magnetic field to penetrate the skull, generate induction current to stimulate neurons and trigger a series of physiological and biochemical responses. rTMS has been applied to the monitoring, evaluation, and treatment of neurological diseases, providing a novel approach to exploring the structure and function of the brain10. Existing studies11,12 have shown that rTMS has varying therapeutic effects on limb spasms and motor function in children with CP. Moreover, the effect of rTMS treatment combined with other rehabilitation techniques is more noticeable.
AOT is a rehabilitation method that utilizes the Mirror Neuron System (MNS) to establish motor learning and memory13,14. The essence of AOT is to make the observer carefully observe actions in the video and subsequently try their best to imitate what they observed. The observing process might trigger activation in the neural network known as MNS, akin to the activation that occurs when one is personally engaged in executing those actions15, which provides a neurophysiological basis for AOT. AOT has shown success in improving motor skills in patients with movement disorders, yielding positive outcomes in stroke recovery and rehabilitation of upper limb motor function in cerebral palsy patients16,17.
Our previous studies have found that AOT based on the mirror neuron system could effectively improve the balance and walking ability of children with cerebral palsy18. In addition, studies19 have shown that rTMS can improve muscle spasticity, movement, and gait in children with SCP, but treatment standards of rTMS applied to children with cerebral palsy have not been unified, and it is an urgent problem to explore the influence of different parameters of rTMS on children with CP, to provide a personalized and precise treatment standard. We believe that combining rTMS with AOT has the potential to develop into a valuable physical therapy strategy for the neurological rehabilitation of cerebral palsy. Both rTMS and AOT stimulated the cerebral cortex in children with SCP20, thereby aiding gross motor function development. This study aimed to find out whether the combination of rTMS and AOT could achieve a greater synergistic effect than conventional treatment or rTMS or AOT alone.
This study was carried out in strict accordance with the national standards for human experimentation, and the clinical study was approved by the Ethics Association of Xiangya Boai Rehabilitation Hospital (ethics approval number: 20211223). The children's guardians agreed to participate in this training program and signed informed consent forms. Children with SCP were recruited in the Xiangya Boai Rehabilitation Hospital and Xiangya Hospital of Central South University from February 2022 to December 2022.
1. Preparation before the experiment
2. Recruitment
3. Pretreatment assessment
4. Therapeutic method
NOTE: Explain the principles and objectives of the training program, as well as possible adverse effects and safety issues during the training process, to the guardians of the children.
5. Post treatment evaluation
NOTE: The pretreatment and 12 week post treatment evaluation for each patient would be completed by the same pediatric rehabilitation doctor.
6. Statistical analysis
This paper presents the results of 64 children with SCP (Supplementary Table S1 and Supplementary File 1), who were randomly divided into four groups according to the numerical table method and given different rehabilitation measures for 12 weeks. During the entire process, the participating children had no adverse reactions such as headaches, dizziness, and seizures.
The demographic data of the four groups of children are shown in Table 1. Before treatment, there were no significant differences in the sex ratio, age, spastic category of cerebral palsy, GMFCS, GDDS developmental quotient (GDDS DQ), and usage of assistive devices (ankle foot orthosis or walker) (all P > 0.05).
The CSS scores of the four groups of children before and after the 12-week treatment have been compared in Table 2. After 12 weeks of training, the CCS scores of all four groups significantly decreased, with the combination intervention group showing significantly greater changes than the other three groups. The time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05).
The scores of PBS, 10MWS, and GMFM before and after the 12-week training of the four groups are shown in Table 3, Table 4, and Table 5. Compared to the pretraining scores, the scores of PBS, 10MWS, and GMFM of all four groups significantly increased after the treatment, with the scores of the combination intervention group improving the most. The time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05).
The clinical effects on gross motor function in all four groups of children are represented in Table 6. The total efficacy rate of gross motor function in the combination intervention group was 87.50%, which was significantly higher than those of the remaining three groups (rTMS group 62.50%, AOT group 68.75%, conventional group 25.00%) (χ2 = 13.850, P = 0.003).
Figure 1: Stimulation of the M1 area. (A) Threshold determination: The value of RMT was measured when the contralateral M1 region corresponding to the abductor pollicis breve muscle, which was stimulated with a single pulse to generate a motion-evoked potential. (B) Low-frequency stimulation on the M1 region of the undamaged cerebral cortex: stimulation frequency was 1Hz, stimulation intensity was 80% RMT, stimulation number was 10, stimulation time lasted for 10 s, the number of repetitions was 80 times, and the total number of pulses was 800. (C) High-frequency stimulation of the M1 region of the damaged cerebral cortex: stimulation frequency was 5 Hz, stimulation intensity was 100% RMT, stimulation number was 15, stimulation time lasted for 3 s, repetition times was 80 times, and the total number of pulses was 1,200. Please click here to view a larger version of this figure.
Figure 2: Action observation training. (A) The first movement: Sit-to-Stop Conversion. (B) The second movement: left/right bodyweight shifting. (C) The third movement: back/forth bodyweight shifting. (D) The fourth movement: left/right body rotation. (E) The fifth movement: left/right walking. (F) The sixth movement: stepping up/down alternatively. Please click here to view a larger version of this figure.
(n=64, x±s) | |||||||||
Item | Conventional Group | rTMS Group | AOT Group | combination intervention group | χ2 /F | P | |||
Number (n) | 16 | 16 | 16 | 16 | |||||
Sex Ratio (Male/Female) | 10/6 | 10/6 | 13/3 | 9/7 | 2.494 | 0.476 | |||
Age (Year) | 4.44±0.80 | 4.74±0.68 | 4.71±0.54 | 4.63±0.68 | 0.654 | 0.683 | |||
Classification of spastic cerebral palsy (spastic hemip legia/spastic dip legia/spastic quadriplegia) | 02-07-2007 | 5/10/1 | 6/9/1 | 5/10/1 | 2.105 | 0.945 | |||
GMFCS (n) (Level I/II/III) | 7/3/6 | 6/5/5 | 8/5/3 | 8/5/3 | 2.750 | 0.868 | |||
GDDS DQ | 70.06±10.25 | 70.13±9.44 | 71.56±12.58 | 69.25±6.89 | 0.148 | 0.931 | |||
Usage of assistive devices (n) Yes/No |
5/11 |
3/13 | 3/13 | 4/12 | 1.780 | 0.699 |
Table 1: Comparison of the basic information of the four groups of children (n = 64, x ± s). *One-way analysis of variance. Before the training, there were no significant differences in sex ratio, age, spastic category of cerebral palsy, GMFCS, GDDS developmental quotient (GDDS DQ), and usage of assistive devices (ankle foot orthosis or walker), indicating comparability. Abbreviations: GMFCS = Gross motor function classification; GDDS DQ = Gesell developmental diagnosis schedule developmental quotient.
Group | Number (n) | BEFORE | AFTER | F | P | ||
Conventional Group | 16 | 10.63±1.67 | 10.19±1.76 | ||||
rTMS Group | 16 | 10.88±1.41 | 9.75±1.13 | ||||
AOT Group | 16 | 10.75±1.13 | 9.75±1.00 | ||||
combination intervention group | 16 | 10.69±1.01 | 8.88±1.02 | ||||
Group Factor | 0.774 | 0.513 | |||||
Time Factor | 228.261 | <0.001 | |||||
Group Factor * Time Factor | 15.217 | <0.001 |
Table 2: Comparison of CSS scores in the four groups of children (n = 64, x ± s). After treatment, repeated-measures ANOVA results showed that the time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05). Abbreviations: CSS = Comprehensive Spasticity Scale; rTMS = repeated transcranial magnetic stimulation; AOT = action observation training.
Group | Number (n) | BEFORE | AFTER | F | P | ||
Conventional Group | 16 | 28.25±9.38 | 31.13±9.22 | ||||
rTMS Group | 16 | 29.44±10.05 | 35.56±9.82 | ||||
AOT Group | 16 | 29.25±9.84 | 35.94±8.62 | ||||
combination intervention group | 16 | 29.81±11.59 | 41.88±8.03 | ||||
Group Factor | 1.12 | 0.348 | |||||
Time Factor | 371.208 | <0.001 | |||||
Group Factor * Time Factor | 27.954 | <0.001 |
Table 3: Comparison of PBS scores in the four groups of children (n = 64, x ± s). After treatment, repeated-measures ANOVA results showed that the time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05). Abbreviations: PBS = Pediatric Balance Scale; rTMS = repeated transcranial magnetic stimulation; AOT = action observation training.
Group | Number (n) | BEFORE | AFTER | F | P | ||
Conventiona Group | 16 | 1.02±0.14 | 1.10±0.16 | ||||
rTMS Group | 16 | 0.98±0.18 | 1.15±0.16 | ||||
AOT Group | 16 | 0.99±0.12 | 1.15±0.09 | ||||
combination intervention group | 16 | 1.02±0.15 | 1.24±0.11 | ||||
Group Factor | 0.946 | 0.424 | |||||
Time Factor | 501.551 | <0.001 | |||||
Group Factor * Time Factor | 19.275 | <0.001 |
Table 4: Comparison of 10MWS scores in the four groups of children (n = 64, x ± s). After treatment, repeated-measures ANOVA results showed that the time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05). Abbreviations: 10MWS = 10 m walking speed; rTMS = repeated transcranial magnetic stimulation; AOT = action observation training.
Group | Number (n) | BEFORE | AFTER | F | P | ||
Conventiona Group | 16 | 46.63±20.05 | 54.00±22.19 | ||||
rTMS Group | 16 | 48.94±19.96 | 61.94±20.61 | ||||
AOT Group | 16 | 50.25±15.25 | 63.63±16.40 | ||||
combination intervention group | 16 | 50.94±18.43 | 75.69±17.86 | ||||
Group Factor | 1.300 | 0.283 | |||||
Time Factor | 502.502 | <0.001 | |||||
Group Factor * Time Factor | 31.184 | <0.001 |
Table 5: Comparison of GMFM scores in the four groups of children (n = 64, x ± s). After treatment, repeated-measures ANOVA results showed that the repeated-measures ANOVA results showed that the time effect and the interaction effect between groups and time were significant (P < 0.05), while the effect between groups was not significant (P > 0.05). Abbreviations: GMFM = gross motor function measure; rTMS = repeated transcranial magnetic stimulation; AOT = action observation training.
Group | Number | obvious effective | Effective | Ineffective | Effective rate | ||
Conventional Group | 16 | 1 | 3 | 12 | 25.00% | ||
rTMS Group | 16 | 3 | 7 | 6 | 62.50% | ||
AOT Group | 16 | 2 | 9 | 5 | 68.75% | ||
combination intervention group | 16 | 7 | 7 | 2 | 87.50% | ||
χ2 | 13.850 | ||||||
P | 0.003 | ||||||
Abbreviations: rTMS = repeated transcranial magnetic stimulation; AOT = action observation training. |
Table 6: Comparison of gross motor function of all four groups of children (n [%]). Abbreviations: rTMS = repeated transcranial magnetic stimulation; AOT = action observation training.
Supplementary File 1: Case information of a patient. The patient was treated with rTMS combined with AOT. After 12 weeks of treatment, the data of various evaluation indicators before and after treatment were compared to determine the clinical effect of the combined intervention on the patient's gross motor function. Please click here to download this File.
Supplementary Table S1: Patient data. Please click here to download this File.
For children with SCP, increased activity of γ and α neurons leads toinhibition of corticospinal tract input, which results in increased muscle tension known as spasm. As limb spasms significantly affect the development of lower limb motor function of children with SCP, one of the crucial training goals is to reduce spasticity. Currently, stepwise treatment strategies are employed to alleviate spasticity, including rehabilitation nursing, physical therapy, orthopedic brace application, botulinum toxin injections27, drug treatments, and surgical interventions28. In this study, rehabilitation techniques such as exercise therapy, hydrotherapy, massage therapy, and rTMS were used to relieve spasms in children with SCP. Table 2 shows that the CSS scores in the combination intervention group exhibited greater improvement than the other three groups, suggesting that combined intervention of rTMS and AOT is more effective in relieving the spasticity of children with SCP. Rajak et al.12 suggested that increasing the frequency of rTMS treatment can help reduce muscle spasms in CP children and facilitate the development of motor function. Gupta et al.29 treated 20 cases of cerebral palsy patients with rTMS at 5 Hz and 10 Hz for 20 days, stimulating the motor cortex of the brain, and results showed that the muscle tension of rTMS treatment was significantly lower than that of the conventional group. This finding was consistent with the result of the present study in which the CSS scores of the experimental group were significantly better than those of the other three groups of children.
Before accepting rTMS treatment, it was necessary to measure the motor threshold of the children first to determine their treatment intensity. For children with spastic hemiplegia, the healthy side was evaluated first, then the affected side. The motor threshold of the healthy side was used to determine the treatment intensity. During rTMS treatment, positioning caps should be worn correctly, the coil stimulation center should coincide with the fixed point determined by the coil, and the coil should be placed at a 45°with the scalp. In this study, the M1 region was selected as a stimulation site to improve lower limb movement disorders. Low-frequency stimulation with 1 Hz frequency can reduce cerebral blood flow and excitability of the stimulation side and increase the excitability of the contralateral side. High-frequency stimulation with 5 Hz frequency could directly improve cortical excitability of the stimulated side. The aim is to achieve better inter-hemispheric inhibition, and alternating low- and high-frequency stimulation is conducive to the recovery of motor function.
AOT represents a promising approach for cerebral palsy intervention, restoring damaged brain networks to re-establish motor function as an adjunct to physiotherapy15,30. According to this mechanism, scholars have explored AOT's synergy with constraint-induced therapy6, whole-body vibration training31, and brain-computer interface systems32 in cerebral palsy rehabilitation. AOT must present meaningful actions to observers and requires children to have a certain cognitive ability to imitate the actions in the video. The key point of AOT was observation, not execution of actions. As balance disorders could affect independent walking and daily activities of children with SCP, enhancing their balance control ability was particularly important. This study incorporated AOT programs involving functional movements to enhance lower limb balance and walking abilities. The children attentively watched the video, and physical therapists informed them of more details of the actions presented in the video and guided and supervised the children to perform the actions correctly. During training, physiotherapists need to elucidate movement details to children and adopt incentives to ensure spontaneous participation. AOT has achieved good therapeutic effects in remote rehabilitation environments for children with CP due to its simple operation33. Therefore, parents are encouraged to implement intensive home-based training to enhance training effectiveness. Meanwhile, the training effectiveness is closely related to the training program that patients adhere to during the observation and/or execution of movements. Different learning and performance outcomes will be produced based on varying attention levels paid to observe the training resources34. Kim et al.35 found no substantial difference when comparing the results of short and long-term AOT interventions.
In this study, on the basis of conventional rehabilitation, the effects of four different ways of intervention, namely, conventional rehabilitation measures alone, rTMS, AOT, and combined intervention of rTMS and AOT, on the gross motor function of Children with SCP were respectively administered to explore whether the combined intervention has a synergistic effect. Table 3, Table 4, and Table 5 illustrate that after 12 weeks of treatment, scores of PBS, 10MWS, and GMFM improved for all groups. However, the combined intervention group exhibited the most substantial enhancement in PBS, 10MWS, and GMFM scores compared to the conventional, rTMS, and AOT groups. Moreover, its gross motor function effective rate was also significantly higher. Table 6 shows that the gross motor function effective rate in the combined intervention group was 87.50%, surpassing the conventional group (25.00%), rTMS group(62.50%), and AOT group (68.75%) (χ2=13.850, P=0.003), suggesting that the combined intervention of rTMS and AOT is more effective in improving the motor function of children with SCP. The regulation mechanisms might be: first, the rTMS site is the M1 region of the lower limb motor region of the cerebral cortex, which is close to the region where AOT activates MNS. Movement observation and execution strengthen the connection between the motor cortex and the M1 region through MNS36. Second, Sun et al.37confirmed that rTMS regulates the excitability of the target cerebral cortex by applying a magnetic field to the target cerebral region to generate an inductive current, which can propagate along the corticospinal tracts and peripheral motor nerves, leading to muscle responses that promote the recovery of limb motor function.AOT can provide children with the expected experience and preparation of the action by first observing the video, and promote the task-dependent neuronal network activity when performing the same task38. Third, rTMS stimulation of lateral motor cortical areas induces trans-synaptic activation of subcortical circuits via induced currents, producing reduced motor and muscle spastic activity to establish correct movement patterns39. Action videos of the AOT program can be observed repeatedly and simultaneously enhance motor memory and promote cerebral cortex remodeling through repeated execution of the program40. The combined intervention could synergistically regulate cortical activity, increase the excitability of the motor cortex and the recruitment of motor units, reduce spasticity and muscle hyperreflexia, and enhance the effect of mutual interaction. For these reasons, rTMS combined with AOT may have a synergistic effect to optimize neuroplastic changes and improve motor function recovery.
The combination of rTMS and AOT emerges as an effective strategy for individualized rehabilitation for lower limb dysfunction in children with SCP, improving balance and motor function. There are also shortcomings in this study: placebo effects may be present for rTMS since a sham rTMS condition was not used. Most of the assessment methods used in the study were rehabilitation assessment scales, and no objective assessment with imaging such as neurophysiology, electroencephalography, or functional MRI was applied. Besides, large-scale, long-term clinical studies and randomized controlled trials with objective neurophysiological or imaging evaluation are required to obtain standardized treatment parameters for rTMS therapy and AOT or to determine the therapeutic effect.
The authors have nothing to disclose.
This study was supported by the funding of the Xiangya Boai Rehabilitation Hospital.
K6 multimedia scene interactive training system | Hunan Le Jiekang technology Co., LTD | Program implementation | |
KLW-SLL type spa machine for children | Nanjing Kanglongwei Technology Industrial Co., LTD | Conventional therapy | |
Pulse magnetic field stimulator model YRD CCY-II | Shenzhen Yingzhi technology Co., LTD | Program implementation | |
SPSS26 software | IBM | Statistic analysis |