Non-invasive TMS attenuates neuropathic pain after spinal cord injury associated with enhancing brain functional connectivity and HPA axis activity
Qing Zhao,
Lijuan Zhao,
Pianpian Fan,
Yanjing Zhu,
Rongrong Zhu,
Liming Cheng,
Ning Xie
Affiliations
Qing Zhao
Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China; Department of Spine Surgery, Center for Orthopaedic Surgery, Academy of Orthopedics, Orthopaedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510665, China
Lijuan Zhao
Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China
Pianpian Fan
Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, 610044, China
Yanjing Zhu
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China
Rongrong Zhu
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China; Corresponding author. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Division of Spine, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, 389 Xincun Rd, Shanghai, 200065, China.
Liming Cheng
Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China; Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, 200065, China; Corresponding author. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Division of Spine, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai, 200065, China.
Ning Xie
Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, China; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200065, China; Corresponding author. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Division of Spine, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Rd, Shanghai, 200065, China.
Patients with spinal cord injury (SCI) often suffer from varying degrees of neuropathic pain.Non-invasive repetitive transcranial magnetic stimulation (TMS) has been shown to improve neuropathic pain, while the appropriate intervention strategies of TMS treatment and how TMS affects brain function after SCI were not entirely clear. To investigate the effects and mechanisms of TMS on neuropathic pain after SCI, high-frequency TMS on primary motor cortex (M1) of mice was performed after SCI and pain response was evaluated through an electronic Von-Frey device and cold/hot plates. Functional magnetic resonance imaging (fMRI), bulk RNA sequencing, immunofluorescence and molecular experiments were used to evaluate brain and spinal cord function changes and mechanisms. TMS significantly improved SCI induced mechanical allodynia, cold and thermal hyperalgesia with a durative effect, and TMS intervention at 1 week after SCI had pain relief advantages than at 2 weeks. TMS intervention not only affected the functional connections between the primary motor cortex and the thalamus, but also increased the close connection of multiple brain regions. Importantly, TMS treatment activated the hypothalamic pituitary adrenal (HPA) axis and increased the transcript levels of genes encode hormone proteins, accompanied with the attenuation of inflammatory microenvironment in spinal cord associated with pain relief. Totally, these results elucidate that early intervention with TMS could improve neuropathic pain after SCI associated with enhancing brain functional connectivity and HPA axis activity which should be harnessed to modulate neuropathic pain after SCI.
