Study protocol of a randomized controlled trial for the synergizing effects of rTMS and Tui Na on upper limb motor function and cortical activity in ischemic stroke

 FYI.

Study protocol of a randomized controlled trial for the synergizing effects of rTMS and Tui Na on upper limb motor function and cortical activity in ischemic stroke

Yu-Feng Chen^1,2, Guang-Yue Zhu³, Meng-Chai Mao^1,4, Ya Zheng³, Hao Huang⁵, Lan-Lan Liu⁵, Si-Yun Chen¹, Ling-Yun Cao¹ and Dong-Sheng Xu^1,4,6*

• ¹School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ²Department of Tui Na, Hangzhou Dingqiao's Hospital, Hangzhou, China
• ³Rehabilitation Medical Center, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
• ⁴Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, China
• ⁵Department of Rehabilitation Medicine, Shanghai Third Rehabilitation Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ⁶Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China

Upper limb motor dysfunction after stroke is a serious threat to the living quality of patients and their families. Recovery of upper limb motor function after stroke largely relies on the activation and remodeling of neural circuits. rTMS (repetitive transcranial magnetic stimulation) has been proved to promote the reconstruction of neural synapses and neural circuits. However, there are still a large number of patients who cannot fully recover and leave behind varying degrees of dysfunction. Considering the systemic pathology after stroke, in addition to focal brain injury, stroke can also cause extensive dysfunction of peripheral organs. The rehabilitation strategy for stroke should combine the treatment of primary brain lesions with the intervention of secondary systemic damage. The aim of this trial is to verify the efficacy of rTMS synergize with Tui Na (Chinese Massage) on upper limb motor function after ischemic stroke, and to explore the mechanism of activation and remodeling of sensorimotor neural circuits with functional near-infrared spectroscopy. Ninety patients will be randomly assigned to either rTMS + Tui Na + conventional rehabilitation group (the experimental group) or rTMS + conventional rehabilitation group (the control group) in 1:1 ratio. Intervention is conducted five sessions a week, with a total of twenty sessions. The primary outcome is Fugl-Meyer Assessment, and the secondary outcomes include Muscle Strength, Modified Ashworth Assessment, Modified Barthel Index Assessment, motor evoked potentials and functional near-infrared spectroscopy. There are four time points for the evaluation, including baseline, 2 weeks and 4 weeks after the start of treatment, and 4 weeks after the end of treatment. This study is a randomized controlled trial. This study was approved by Institutional Ethics Committee of Shanghai Third Rehabilitation Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (approval No. SH3RH-2021-EC-012) on December, 16th, 2021. The protocol was registered with Chinese Clinical Trial Registry (ChiCTR2200056266), on February 3th, 2022. Patient recruitment was initiated on February 10th, 2022, and the study will be continued until December 2023.

Background

Epidemiological investigation shows that stroke seriously threatens safety and quality of life in the world (1). Ischemic stroke accounts for a higher proportion than that of hemorrhagic stroke. Most patients have motor dysfunction, especially upper limb (UL) motor dysfunction after stroke (2). UL movement is more delicate and complex, and its unsatisfactory recovery can reduce patients' activities of daily life and seriously affect the living quality of patients and their families (3). Therefore, UL motor dysfunction is a key and challenging point in rehabilitation after stroke.

Transcranial magnetic stimulation (TMS) is a neuromodulation technique for treating nervous and mental diseases in recent years. Repetitive transcranial magnetic stimulation (rTMS) is a continuous, repetitive mode of TMS, and it has been proved that rTMS has a good effect on neurological disorders. The latest guideline in 2019 recommended TMS as an A level for treating UL motor dysfunction in subacute stroke (4). Research has shown that rTMS can promote the regulation of microenvironmental factors, glial cell activity, and nerve fiber myelin sheath repair in the injured area, and promote the reconstruction of neural synapses and neural circuits (5–7). However, there are still a large number of patients who cannot fully recover and leave behind varying degrees of dysfunction (8). Therefore, while continuously improving the technology of rTMS, such as accuracy and treatment depth, it is necessary to find other methods to synergize with rTMS to enhance the therapeutic effect. Currently, there are some deficiencies in the combination between rTMS and other treatments (such as neuromuscular electrical stimulation, physical therapy and occupational therapy). The treatment mainly focuses on the brain and limbs, but does not pay attention to the influence of systemic pathology on the recovery of UL, and there is no good intervention method for systemic pathological injury (9).

Considering the systemic pathology after stroke, in addition to focal brain injury, stroke can also cause extensive dysfunction of peripheral organs. Stroke will profoundly change the autonomic nervous system, hypothalamus-pituitary-adrenal axis, immune system and fascia and muscle system, resulting in further systemic damage (10). In turn, systemic pathological changes after stroke promote the progress and prognosis of brain injury to a great extent. Especially in the elderly, it usually leads to more serious systemic damage and a worse prognosis after stroke (9). Before the stroke, the central and peripheral organ systems of a large number of elderly patients have been affected by varying degrees of structural and functional degradation because of continuous exposure to normal aging or chronic low-grade systemic inflammation and other pathological backgrounds. All of these “silent” pathology before stroke have laid the foundation for the emergence of systemic abnormalities caused by stroke (9). After the stroke, excitotoxicity, neuroinflammation, energy disturbance, oxidative stress, and other pathological processes work together, combined with previous complications, to cause or aggravate the structural changes and functional damage of multiple peripheral organs (11). Therefore, stroke should be regarded as a systemic disease with a profound impact on the surrounding organs. The rehabilitation strategy for stroke should combine the treatment of primary brain lesions with the intervention of secondary systemic damage.

Tui Na (Chinese massage therapy) is a relatively simple, inexpensive and non-invasive intervention, and has been used to treat stroke patients for many years in China(appeal to antiquity is not valid). Tui Na mainly acts on specific parts of the body through manipulation, on the one hand, it plays a local therapeutic role in the body, on the other hand, it can also have a certain impact on various systems of the body through nerves, body fluids and other ways, so as to achieve the role of treating diseases (12). Clinical observation suggested that Tui Na might be a safe and effective treatment for post-stroke UL motor dysfunction (13, 14). Although the mechanism of Tui Na on treatment of post-stroke motor dysfunction is limited, some possible mechanism was proposed. Tui Na manipulation stretched the muscle–tendon complex and stimulate the Golgi tendon organ that could inhibit alpha motor neurons and reduce spasm (15). Tui Na manipulation might reinforce sensory stimulation and activate the gamma efferent fibers of muscle stretch receptors that make receptors more sensitive to stretch (15). Soreness and distension that was caused by Tui Na manipulation will excite the sensory cortex, thus inhibit reticular formation of brainstem and decrease the muscle tone (15). For more than two thousand years, traditional Chinese medicine therapists have been using Tui Na act on governor meridian-related acupoints to treat spinal-related diseases and many visceral disorders (16). The spine is the pillar of the human body and the medium that connects the brain and the peripheral organs. The spine is the pathway of the governor meridian in traditional Chinese medicine, which dominates people's life activities (17). The spine contains the spinal cord, with spinal nerves and sympathetic pathways on both sides. Although there are great differences in theory and technology between traditional Chinese and western medicine, they are almost the same in understanding the importance of the spine and preventing and treating diseases by adjusting the spine and its related surrounding tissues.

Based on the above research background, we adopt the strategy of rTMS to synergize with Tui Na to promote the recovery of UL motor dysfunction after ischemic stroke. fNIRS (functional near-infrared spectroscopy) will be used as a technique for sensorimotor cortex activity monitoring and brain plasticity evaluation. The function of Tui Na is reflected in two aspects:1. Tui Na will be used to stimulate the peripheral sensory nerve, promote the activation of the cortical sensorimotor network, and then activate the corticospinal tract with rTMS from the cortical motor area (M1) aimed at the reconstruction of “sensory afferent-cortical integration-motor execution,” in order to obtain the effect of synergy-enhancement. 2. The extensive effects of Tui Na on autonomic nerve, fascia and muscle system can promote the function of a wide range of peripheral organs, to promote the prognosis of stroke. Therefore, our primary objective was to identify a protocol for a randomized controlled trial to evaluate the effects of rTMS synergizing with Tui Na on the motor function of the UL in patients with ischemic stroke. We hypothesized that the treatment of rTMS synergized with Tui Na can promote the improvement of UL motor function after ischemic stroke and activate and remodel sensorimotor cortex activity.