• Duncan J Hodkinson, Marianne M Drabek, JeYoung Jung, Sudheer T Lankappa, and Dorothee P Auer.
• Division of Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, UK; Sir Peter Mansfield Imaging Center, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research, Nottingham Biomedical Research Center, Queens Medical Center, Nottingham, UK. Electronic address: duncan.hodkinson@nottingham.ac.uk.
• Neuromodulation. 2024 Jul 1; 27 (5): 812823812-823.

ObjectivesMany chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols.Materials And MethodsIn a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states. Secondary hyperalgesia (a form of use-dependent central sensitization) was induced using a well-established injury-free pain model and assessed by standardized quantitative sensory testing involving light touch and pinprick pain thresholds in addition to stimulus-response functions.ResultsWe found that continuous TBS of the human motor cortex has a facilitatory (pronociceptive) effect on the magnitude of perceived pain to secondary hyperalgesia, which may rely on induction and expression of neural plasticity through heterosynaptic long-term potentiation-like mechanisms.ConclusionsBy defining the underlying mechanisms of TBS-driven synaptic plasticity in the nociceptive system, we offer new insight into disease mechanisms and provide targets for promoting functional recovery and repair in chronic pain. For clinical applications, this knowledge is critical for development of more efficacious and mechanisms-based neuromodulation protocols, which are urgently needed to address the chronic pain and opioid epidemics.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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